NM_001146079.2:c.488C>T

Variant names:

• chr21-36461208-G-A
• rs143797113
• NM_001146079.2:c.488C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B.

Score: 7 - Likely Pathogenic

7

PP5_Very_StrongBS1_Supporting

The NM_001146079.2(CLDN14):​c.488C>T​(p.Ala163Val) variant causes a missense change. The variant allele was found at a frequency of 0.000712 in 1,614,124 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (1 hom.)
• Consequence: CLDN14 NM_001146079.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 U:1
• Conservation: PhyloP100: 5.45
• Publications: 11 publications found

Genes affected

CLDN14 (HGNC:2035): (claudin 14) Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. These junctions are comprised of sets of continuous networking strands in the outwardly facing cytoplasmic leaflet, with complementary grooves in the inwardly facing extracytoplasmic leaflet. The protein encoded by this gene, a member of the claudin family, is an integral membrane protein and a component of tight junction strands. The encoded protein also binds specifically to the WW domain of Yes-associated protein. Defects in this gene are the cause of an autosomal recessive form of nonsyndromic sensorineural deafness. It is also reported that four synonymous variants in this gene are associated with kidney stones and reduced bone mineral density. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jun 2010]

LNCTSI (HGNC:56660): (lncRNA TGF-beta/SMAD3 pathway interacting)

CLDN14-AS1 (HGNC:55953): (CLDN14 antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PP5: Variant 21-36461208-G-A is Pathogenic according to our data. Variant chr21-36461208-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000741 (1083/1461770) while in subpopulation NFE AF = 0.00094 (1045/1111972). AF 95% confidence interval is 0.000892. There are 1 homozygotes in GnomAdExome4. There are 523 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN14	NM_001146079.2	c.488C>T	p.Ala163Val	missense_variant	Exon 2 of 2	ENST00000399135.6	NP_001139551.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN14	ENST00000399135.6	c.488C>T	p.Ala163Val	missense_variant	Exon 2 of 2	1	NM_001146079.2	ENSP00000382087.1

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000292 AC: 73 AN: 249754 AF XY: 0.000326

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000588

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000741 AC: 1083 AN: 1461770 Hom.: 1 Cov.: 34 AF XY: 0.000719 AC XY: 523 AN XY: 727186

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000940 AC: 1045 AN: 1111972

Other (OTH) AF: 0.000513 AC: 31 AN: 60394

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74500

African (AFR) AF: 0.000192 AC: 8 AN: 41590

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000581 Hom.: 2

Bravo AF: 0.000427

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000436

EpiControl AF: 0.000771

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 29 Pathogenic:6

Mar 02, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jul 09, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM3, PP1, PP3 -

Jun 21, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CLDN14 c.488C>T (p.Ala163Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 249754 control chromosomes (gnomAD), and is commonly reported in individuals of Newfoundland ancestry due to a founder effect (Pater_2017). c.488C>T has been reported in the literature in several individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss, including one compound heterozygous individual (Sloan-Heggen_2016) and several homozygous individuals from 2 unrelated Newfoundland families (Pater_2017). All homozygous individuals had a unique audioprofile that distinguised them from heterozygous and non-carrier family members with unexplained hearing loss (Pater_2017). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters have assessed the variant since 2014: one classified the variant as VUS, two as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 01, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CLDN14 c.488C>T (p.Ala163Val) missense variant was identified in a compound heterozygous state with a second missense variant in one individual with nonsyndromic hearing loss (Sloan-Heggen et al. 2016). Pater et al (2017) reported the p.Ala163Val variant in a very large family from Newfoundland that was originally thought to be three separate families but detailed pedigree analysis revealed common ancestors. All ten individuals from this extended family with a rare audioprofile were found to be homozygous for the p.Ala163Val variant. A different audioprofile was identified in five additional individuals in the family with hearing loss. Of these five, one carried the p.Ala163Val variant in a heterozygous state; the remaining four did not carry this variant, and the authors suggest a second cause of hearing loss within the family. Seven additional unaffected members of this family were heterozygous for the p.Ala163Val variant. Analysis by Pater et al. (2017) of additional hearing loss families in Newfoundland revealed the variant in a homozygous state in two related individuals with the same audioprofile as the homozygotes from the extended family, and in a heterozygous state in two further unrelated individuals with hearing loss. The variant was also found in a heterozygous state in an unaffected relative of the two homozygotes. The p.Ala163Val variant was identified in a heterozygous state in four of 175 normal-hearing controls (Pater et al. 2017) and is reported at a frequency of 0.00070 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Ala163Val variant is classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Feb 14, 2023

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (C>T) at coding position 488 of the CLDN14 gene that results in an alanine to valine amino acid change at residue 163 of the CLDN14 encoded protein, Claudin-14. The Ala163 residue falls in the fourth transmembrane domain (PMID: 27838790). This is a previously reported variant (ClinVar) that has been observed in homozygous and compound heterozygous individuals affected by hearing loss. The alysis of 3 families spanning multiple generations found that this variant, in the homozygous state, associates with hearing loss. This variant is present in 89 of 281,138 (0.03%) alleles in the gnomAD population database. In addition, it is believed to be a founder variant in the Newfoundland island population. Multiple bioinformatic tools predict that this alanine to valine amino acid change would be damaging, and the alanine residue at this position is strongly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been published, to our knowledge. We consider this a likely pathogenic variant. ACMG Criteria: PM1, PP1, PP3 -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness 29 (MIM#614035). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (89 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated fourth transmembrane domain (PMID: 27838790). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as a VUS, but has more recently and consistently been classified as likely pathogenic or pathogenic (ClinVar, deafnessvariationdatabase.org). It has been observed in a compound heterozygous individual with congenital-onset nonsyndromic hearing loss (NSHL), and is regarded as a Newfoundland founder variant, having been observed in many homozygous individuals with mid-high frequency NSHL (PMID: 27838790, PMID: 26969326). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been observed in a total of twelve homozygous individuals, all linked through haplotype mapping to be part of a single large family (PMID: 27838790). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 163 of the CLDN14 protein (p.Ala163Val). This variant is present in population databases (rs143797113, gnomAD 0.06%). This missense change has been observed in individual(s) with autosomal recessive nonsyndromic deafness (PMID: 27838790). It is commonly reported in individuals of Newfoundland ancestry (PMID: 27838790). ClinVar contains an entry for this variant (Variation ID: 228519). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Feb 28, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with a pathogenic CLDN14 variant in a patient with hearing loss in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 26969326); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29447821, 23991001, 36147510, 36833326, 38790217, 27838790, 26969326) -

not specified Uncertain:1

Oct 23, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

The p.Ala163Val variant in CLDN14 has been previously reported by our laboratory in 1 individual with hearing loss; however, a variant affecting the remaining c opy of CLDN14 was not identified (LMM unpublished data). The variant has been id entified in 29/66382 European chromosomes by the Exome Aggregation Consortium (E xAC, http://exac.broadinstitute.org; dbSNP rs143797113). Although this variant h as been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is no t predictive enough to determine pathogenicity. In summary, the clinical signifi cance of the p.Ala163Val variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;D;D;D;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	.;.;.;.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.72	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H;H;H;H;H
PhyloP100		5.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0050	D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.77
MVP		0.94
MPC		0.93
ClinPred		0.89	D
GERP RS		5.4
Varity_R		0.90
gMVP		0.86
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs143797113; hg19: chr21-37833506;