rs219779

Positions:

chr21-36461453-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001146079.2(CLDN14):c.243C>T(p.Arg81=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,613,114 control chromosomes in the GnomAD database, including 50,317 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5073 hom., cov: 33)

Exomes 𝑓: 0.24 ( 45244 hom. )

Consequence

CLDN14
NM_001146079.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.13

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 21-36461453-G-A is Benign according to our data. Variant chr21-36461453-G-A is described in ClinVar as [Benign]. Clinvar id is 44084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-36461453-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.13 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLDN14	NM_001146079.2 linkuse as main transcript	c.243C>T	p.Arg81=	synonymous_variant	2/2	ENST00000399135.6
CLDN14-AS1	NR_183529.1 linkuse as main transcript	n.468+15446G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CLDN14	ENST00000399135.6 linkuse as main transcript	c.243C>T	p.Arg81=	synonymous_variant	2/2	1	NM_001146079.2	P1
CLDN14-AS1	ENST00000428667.1 linkuse as main transcript	n.277+15446G>A		intron_variant, non_coding_transcript_variant		5
LNCTSI	ENST00000429588.1 linkuse as main transcript	n.54-18778G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.250

AC:

37944

AN:

152062

Hom.:

5055

Cov.:

show subpopulations

Gnomad AFR

AF:

0.310

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.228

Gnomad ASJ

AF:

0.236

Gnomad EAS

AF:

0.00771

Gnomad SAS

AF:

0.147

Gnomad FIN

AF:

0.211

Gnomad MID

AF:

0.323

Gnomad NFE

AF:

0.251

Gnomad OTH

AF:

0.260

GnomAD3 exomes

AF:

0.212

AC:

52925

AN:

249378

Hom.:

6248

AF XY:

0.210

AC XY:

28388

AN XY:

135184

show subpopulations

Gnomad AFR exome

AF:

0.304

Gnomad AMR exome

AF:

0.194

Gnomad ASJ exome

AF:

0.238

Gnomad EAS exome

AF:

0.00534

Gnomad SAS exome

AF:

0.157

Gnomad FIN exome

AF:

0.206

Gnomad NFE exome

AF:

0.252

Gnomad OTH exome

AF:

0.222

GnomAD4 exome

AF:

0.242

AC:

354123

AN:

1460934

Hom.:

45244

Cov.:

AF XY:

0.239

AC XY:

173901

AN XY:

726808

show subpopulations

Gnomad4 AFR exome

AF:

0.309

Gnomad4 AMR exome

AF:

0.197

Gnomad4 ASJ exome

AF:

0.236

Gnomad4 EAS exome

AF:

0.00768

Gnomad4 SAS exome

AF:

0.158

Gnomad4 FIN exome

AF:

0.210

Gnomad4 NFE exome

AF:

0.259

Gnomad4 OTH exome

AF:

0.235

GnomAD4 genome

AF:

0.250

AC:

38010

AN:

152180

Hom.:

5073

Cov.:

AF XY:

0.243

AC XY:

18076

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.310

Gnomad4 AMR

AF:

0.228

Gnomad4 ASJ

AF:

0.236

Gnomad4 EAS

AF:

0.00773

Gnomad4 SAS

AF:

0.148

Gnomad4 FIN

AF:

0.211

Gnomad4 NFE

AF:

0.251

Gnomad4 OTH

AF:

0.258

Alfa

AF:

0.254

Hom.:

3552

Bravo

AF:

0.251

Asia WGS

AF:

0.109

AC:

382

AN:

3478

EpiCase

AF:

0.251

EpiControl

AF:

0.251

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Arg81Arg 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 31.1% (1163/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs219779). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 29

Benign:2

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.2

DANN

Benign

0.88

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