21-36461009-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001146079.2(CLDN14):c.687G>A(p.Thr229Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,612,880 control chromosomes in the GnomAD database, including 32,630 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3182 hom., cov: 32)

Exomes 𝑓: 0.19 ( 29448 hom. )

Consequence

CLDN14
NM_001146079.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.16

Publications

53 publications found

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:

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

LNCTSI links:

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

CLDN14-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 21-36461009-C-T is Benign according to our data. Variant chr21-36461009-C-T is described in ClinVar as Benign. ClinVar VariationId is 44088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.16 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN14	NM_001146079.2 link	c.687G>A	p.Thr229Thr	synonymous_variant	Exon 2 of 2	ENST00000399135.6	NP_001139551.1	O95500

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN14	ENST00000399135.6 link	c.687G>A	p.Thr229Thr	synonymous_variant	Exon 2 of 2	1	NM_001146079.2	ENSP00000382087.1		O95500

Frequencies

GnomAD3 genomes

AF:

0.196

AC:

29802

AN:

152002

Hom.:

3175

Cov.:

show subpopulations

Gnomad AFR

AF:

0.242

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.137

Gnomad ASJ

AF:

0.187

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0981

Gnomad FIN

AF:

0.200

Gnomad MID

AF:

0.190

Gnomad NFE

AF:

0.204

Gnomad OTH

AF:

0.205

GnomAD2 exomes

AF:

0.163

AC:

40650

AN:

250066

AF XY:

0.161

show subpopulations

Gnomad AFR exome

AF:

0.241

Gnomad AMR exome

AF:

0.0960

Gnomad ASJ exome

AF:

0.197

Gnomad EAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.195

Gnomad NFE exome

AF:

0.205

Gnomad OTH exome

AF:

0.166

GnomAD4 exome

AF:

0.194

AC:

284010

AN:

1460760

Hom.:

29448

Cov.:

AF XY:

0.191

AC XY:

139110

AN XY:

726670

show subpopulations

African (AFR)

AF:

0.242

AC:

8105

AN:

33458

American (AMR)

AF:

0.100

AC:

4469

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.193

AC:

5032

AN:

26136

East Asian (EAS)

AF:

0.000806

AC:

AN:

39694

South Asian (SAS)

AF:

0.104

AC:

8964

AN:

86214

European-Finnish (FIN)

AF:

0.196

AC:

10464

AN:

53402

Middle Eastern (MID)

AF:

0.161

AC:

817

AN:

5074

European-Non Finnish (NFE)

AF:

0.212

AC:

235258

AN:

1111792

Other (OTH)

AF:

0.180

AC:

10869

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

13348

26696

40044

53392

66740

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8044

16088

24132

32176

40220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.196

AC:

29849

AN:

152120

Hom.:

3182

Cov.:

AF XY:

0.191

AC XY:

14219

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.242

AC:

10039

AN:

41498

American (AMR)

AF:

0.136

AC:

2085

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.187

AC:

649

AN:

3468

East Asian (EAS)

AF:

0.00135

AC:

AN:

5170

South Asian (SAS)

AF:

0.0988

AC:

476

AN:

4820

European-Finnish (FIN)

AF:

0.200

AC:

2119

AN:

10586

Middle Eastern (MID)

AF:

0.197

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.204

AC:

13874

AN:

67968

Other (OTH)

AF:

0.204

AC:

430

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1218

2435

3653

4870

6088

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

316

632

948

1264

1580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.202

Hom.:

8269

Bravo

AF:

0.193

Asia WGS

AF:

0.0780

AC:

274

AN:

3478

EpiCase

AF:

0.203

EpiControl

AF:

0.199

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 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. -

Nov 11, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 29

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.73

(source)

DANN

Benign

0.77

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over