rs117560775

Variant names:

• chr21-36461633-C-T
• rs117560775
• NM_001146079.2:c.63G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001146079.2(CLDN14):​c.63G>A​(p.Thr21Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 1,585,838 control chromosomes in the GnomAD database, including 849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (75 hom., cov: 33)
  • Exomes 𝑓: 0.029 (774 hom.)
• Consequence: CLDN14 NM_001146079.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.64

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:):

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

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

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 21-36461633-C-T is Benign according to our data. Variant chr21-36461633-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 44087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN14	NM_001146079.2	c.63G>A	p.Thr21Thr	synonymous_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.63G>A	p.Thr21Thr	synonymous_variant	Exon 2 of 2	1	NM_001146079.2	ENSP00000382087.1

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3540 AN: 152084 Hom.: 74 Cov.: 33

Gnomad AFR AF: 0.00548

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0671

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.00651

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0284

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0303 AC: 5988 AN: 197896 Hom.: 163 AF XY: 0.0293 AC XY: 3152 AN XY: 107588

Gnomad AFR exome AF: 0.00621

Gnomad AMR exome AF: 0.0833

Gnomad ASJ exome AF: 0.0286

Gnomad EAS exome AF: 0.0000706

Gnomad SAS exome AF: 0.0227

Gnomad FIN exome AF: 0.00659

Gnomad NFE exome AF: 0.0280

Gnomad OTH exome AF: 0.0324

GnomAD4 exome AF: 0.0290 AC: 41546 AN: 1433636 Hom.: 774 Cov.: 33 AF XY: 0.0287 AC XY: 20407 AN XY: 711016

Gnomad4 AFR exome AF: 0.00522

Gnomad4 AMR exome AF: 0.0802

Gnomad4 ASJ exome AF: 0.0311

Gnomad4 EAS exome AF: 0.0000792

Gnomad4 SAS exome AF: 0.0235

Gnomad4 FIN exome AF: 0.00832

Gnomad4 NFE exome AF: 0.0302

Gnomad4 OTH exome AF: 0.0274

GnomAD4 genome AF: 0.0233 AC: 3541 AN: 152202 Hom.: 75 Cov.: 33 AF XY: 0.0228 AC XY: 1697 AN XY: 74400

Gnomad4 AFR AF: 0.00551

Gnomad4 AMR AF: 0.0671

Gnomad4 ASJ AF: 0.0346

Gnomad4 EAS AF: 0.000968

Gnomad4 SAS AF: 0.0205

Gnomad4 FIN AF: 0.00651

Gnomad4 NFE AF: 0.0284

Gnomad4 OTH AF: 0.0256

Alfa AF: 0.0250 Hom.: 23

Bravo AF: 0.0262

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thr21Thr in Exon 03 of CLDN14: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 2.8% (200/7018) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs117560775). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 16, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 29 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.62
CADD	Benign	6.5
DANN	Benign	0.84

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: rs117560775; hg19: chr21-37833931; COSMIC: COSV59774438; COSMIC: COSV59774438;