rs143797113

Positions:

• chr21-36461208-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1 PM2 PP5_Very_Strong BS1_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:5 U:1
• Conservation: PhyloP100: 5.45

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]

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

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

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a chain Claudin-14 (size 238) in uniprot entity CLD14_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) in NM_001146079.2
• PM2: Very rare variant in population databases, with high coverage
• 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. gnomad4_exome 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 gnomad4_exome. There are 523 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLDN14	NM_001146079.2	c.488C>T	p.Ala163Val	missense_variant	2/2	ENST00000399135.6
CLDN14-AS1	NR_183529.1	n.468+15201G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLDN14	ENST00000399135.6	c.488C>T	p.Ala163Val	missense_variant	2/2	1	NM_001146079.2	P1
CLDN14-AS1	ENST00000428667.1	n.277+15201G>A		intron_variant, non_coding_transcript_variant		5
LNCTSI	ENST00000429588.1	n.54-19023G>A		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes AF: 0.000292 AC: 73 AN: 249754 Hom.: 0 AF XY: 0.000326 AC XY: 44 AN XY: 134988

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 SAS 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

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000940

Gnomad4 OTH exome AF: 0.000513

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

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000722 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:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 29 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 01, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 21, 2022	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. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2023	Observed with a second CLDN14 variant in a patient with hearing loss in published literature (Sloan-Heggen et al., 2016); 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, 27838790, 26969326, 36147510, 36833326) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 29, 2023	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 228519). 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). This variant is present in population databases (rs143797113, gnomAD 0.06%). 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). -

not specified Uncertain:1

Uncertain significance, flagged submission

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 23, 2015

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
MutationTaster	Benign	1.0	D;D;D;D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs143797113; hg19: chr21-37833506;