rs113831133

Variant names:

• chr21-36461685-G-A
• rs113831133
• NM_001146079.2:c.11C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 16/21 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
• Publications: 19 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: Benign. The variant received -20 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146079.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN14	NM_001146079.2	MANE Select	c.11C>T	p.Thr4Met	missense	Exon 2 of 2	NP_001139551.1
	CLDN14	NM_001146077.2		c.11C>T	p.Thr4Met	missense	Exon 3 of 3	NP_001139549.1
	CLDN14	NM_001146078.3		c.11C>T	p.Thr4Met	missense	Exon 3 of 3	NP_001139550.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN14	ENST00000399135.6	TSL:1 MANE Select	c.11C>T	p.Thr4Met	missense	Exon 2 of 2	ENSP00000382087.1
	CLDN14	ENST00000342108.2	TSL:1	c.11C>T	p.Thr4Met	missense	Exon 3 of 3	ENSP00000339292.2
	CLDN14	ENST00000399136.5	TSL:1	c.11C>T	p.Thr4Met	missense	Exon 3 of 3	ENSP00000382088.1

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

GnomAD2 exomes AF: 0.0245 AC: 3678 AN: 150242 AF XY: 0.0248

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 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

African (AFR) AF: 0.102 AC: 3242 AN: 31674

American (AMR) AF: 0.0195 AC: 702 AN: 35916

Ashkenazi Jewish (ASJ) AF: 0.0126 AC: 317 AN: 25198

East Asian (EAS) AF: 0.00718 AC: 257 AN: 35810

South Asian (SAS) AF: 0.0320 AC: 2545 AN: 79482

European-Finnish (FIN) AF: 0.00693 AC: 332 AN: 47914

Middle Eastern (MID) AF: 0.0587 AC: 309 AN: 5260

European-Non Finnish (NFE) AF: 0.0213 AC: 22967 AN: 1080252

Other (OTH) AF: 0.0330 AC: 1916 AN: 58022

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

African (AFR) AF: 0.104 AC: 4321 AN: 41568

American (AMR) AF: 0.0284 AC: 434 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3468

East Asian (EAS) AF: 0.00502 AC: 26 AN: 5178

South Asian (SAS) AF: 0.0302 AC: 146 AN: 4830

European-Finnish (FIN) AF: 0.00536 AC: 57 AN: 10628

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0218 AC: 1481 AN: 68030

Other (OTH) AF: 0.0445 AC: 94 AN: 2114

Alfa AF: 0.0236 Hom.: 102

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

Dec 07, 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.

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 02, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 12, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive nonsyndromic hearing loss 29 Benign:2

Jan 12, 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.

Nov 01, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.45	N
PhyloP100		0.66
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.75	N
REVEL	Benign	0.17
Sift	Benign	0.36	T
Sift4G	Benign	0.77	T
Polyphen		0.32	B
Vest4		0.014
MPC		0.28
ClinPred		0.0054	T
GERP RS		3.6
Varity_R		0.026
gMVP		0.45
Mutation Taster		=100/0	polymorphism (auto)

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: rs113831133; hg19: chr21-37833983; COSMIC: COSV107407383; COSMIC: COSV107407383;