rs74315438

Positions:

chr21-36461395-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The ENST00000399135.6(CLDN14):c.301G>A(p.Gly101Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

CLDN14
ENST00000399135.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 7.80

Variant links:

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 links:

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

CLDN14-AS1 links:

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

LNCTSI links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity CLD14_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in ENST00000399135.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 21-36461395-C-T is Pathogenic according to our data. Variant chr21-36461395-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4852.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN14	NM_001146079.2 linkuse as main transcript	c.301G>A	p.Gly101Arg	missense_variant	2/2	ENST00000399135.6	NP_001139551.1
CLDN14-AS1	NR_183529.1 linkuse as main transcript	n.468+15388C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CLDN14	ENST00000399135.6 linkuse as main transcript	c.301G>A	p.Gly101Arg	missense_variant	2/2	1	NM_001146079.2	ENSP00000382087	P1
CLDN14-AS1	ENST00000428667.1 linkuse as main transcript	n.277+15388C>T		intron_variant, non_coding_transcript_variant		5
LNCTSI	ENST00000429588.1 linkuse as main transcript	n.54-18836C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000404

AC:

AN:

247596

Hom.:

AF XY:

0.0000447

AC XY:

AN XY:

134184

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.0000813

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1460888

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

726778

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000351

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000581

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 29

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2005	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2024	Published functional studies suggest the variant may impair polymerization of the CLDN14 protein and interfere with the formation of tight junction strands, however additional studies are needed to determine the significance of this effect (Wattenhofer M et al., 2005); 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: 34426522, 31589614, 31527509, 27838790, 22246673, 24752540, 29447821, 15880785, 38790217, 33105617) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 17, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 101 of the CLDN14 protein (p.Gly101Arg). This variant is present in population databases (rs74315438, gnomAD 0.008%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects CLDN14 function (PMID: 15880785). 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: 4852). This missense change has been observed in individual(s) with deafness (PMID: 15880785, 33105617; Invitae). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;D;D;D;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;.;.;.;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.1

H;H;H;H;H

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.9

D;D;D;D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.98

MutPred

0.91

Gain of MoRF binding (P = 0.0769);Gain of MoRF binding (P = 0.0769);Gain of MoRF binding (P = 0.0769);Gain of MoRF binding (P = 0.0769);Gain of MoRF binding (P = 0.0769);

MVP

0.96

MPC

1.0

ClinPred

1.0

GERP RS

5.4

Varity_R

0.92

gMVP

0.97

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over