rs113831133

Positions:

• chr21-36461685-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001146079.2(CLDN14):​c.11C>T​(p.Thr4Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,551,856 control chromosomes in the GnomAD database, including 843 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T4A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.044 (272 hom., cov: 33)
  • Exomes 𝑓: 0.023 (571 hom.)
• Consequence: CLDN14 NM_001146079.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.662

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 Benign. Variant got -18 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.0014111996).
• BP6: Variant 21-36461685-G-A is Benign according to our data. Variant chr21-36461685-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLDN14	NM_001146079.2	c.11C>T	p.Thr4Met	missense_variant	2/2	ENST00000399135.6
CLDN14-AS1	NR_183529.1	n.468+15678G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLDN14	ENST00000399135.6	c.11C>T	p.Thr4Met	missense_variant	2/2	1	NM_001146079.2	P1
CLDN14-AS1	ENST00000428667.1	n.277+15678G>A		intron_variant, non_coding_transcript_variant		5
LNCTSI	ENST00000429588.1	n.54-18546G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0436 AC: 6633 AN: 152210 Hom.: 272 Cov.: 33

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0284

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.0300

Gnomad FIN AF: 0.00536

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0218

Gnomad OTH AF: 0.0449

GnomAD3 exomes AF: 0.0245 AC: 3678 AN: 150242 Hom.: 84 AF XY: 0.0248 AC XY: 1998 AN XY: 80574

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.0172

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.00472

Gnomad SAS exome AF: 0.0344

Gnomad FIN exome AF: 0.00552

Gnomad NFE exome AF: 0.0232

Gnomad OTH exome AF: 0.0300

GnomAD4 exome AF: 0.0233 AC: 32587 AN: 1399528 Hom.: 571 Cov.: 33 AF XY: 0.0233 AC XY: 16078 AN XY: 690658

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.0195

Gnomad4 ASJ exome AF: 0.0126

Gnomad4 EAS exome AF: 0.00718

Gnomad4 SAS exome AF: 0.0320

Gnomad4 FIN exome AF: 0.00693

Gnomad4 NFE exome AF: 0.0213

Gnomad4 OTH exome AF: 0.0330

GnomAD4 genome AF: 0.0436 AC: 6642 AN: 152328 Hom.: 272 Cov.: 33 AF XY: 0.0417 AC XY: 3110 AN XY: 74498

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0284

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.00502

Gnomad4 SAS AF: 0.0302

Gnomad4 FIN AF: 0.00536

Gnomad4 NFE AF: 0.0218

Gnomad4 OTH AF: 0.0445

Alfa AF: 0.0236 Hom.: 82

Bravo AF: 0.0475

TwinsUK AF: 0.0221 AC: 82

ALSPAC AF: 0.0208 AC: 80

ESP6500AA AF: 0.0945 AC: 402

ESP6500EA AF: 0.0180 AC: 149

ExAC AF: 0.0169 AC: 1728

Asia WGS AF: 0.0250 AC: 88 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Thr4Met in Exon 03 of CLDN14: This variant is not expected to have clinical sign ificance because it has been identified in 9.1% (328/3592) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs113831133). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -

Autosomal recessive nonsyndromic hearing loss 29 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.84
DEOGEN2	Benign	0.033	T;T;T;T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.62	.;.;.;.;T
MetaRNN	Benign	0.0014	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.45	N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.75	N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.36	T;T;T;T;T
Sift4G	Benign	0.77	T;T;T;T;T
Polyphen		0.32	B;B;B;B;B
Vest4		0.014
MPC		0.28
ClinPred		0.0054	T
GERP RS		3.6
Varity_R		0.026
gMVP		0.45

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: rs113831133; hg19: chr21-37833983;