rs727504989

Positions:

chr21-36461613-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_001146079.2(CLDN14):c.83C>T(p.Pro28Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,601,958 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P28P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

CLDN14
NM_001146079.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.87

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 6 ACMG points.

PM1

In a chain Claudin-14 (size 238) in uniprot entity CLD14_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) in NM_001146079.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLDN14	NM_001146079.2 linkuse as main transcript	c.83C>T	p.Pro28Leu	missense_variant	2/2	ENST00000399135.6
CLDN14-AS1	NR_183529.1 linkuse as main transcript	n.468+15606G>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.83C>T	p.Pro28Leu	missense_variant	2/2	1	NM_001146079.2	P1
CLDN14-AS1	ENST00000428667.1 linkuse as main transcript	n.277+15606G>A		intron_variant, non_coding_transcript_variant		5
LNCTSI	ENST00000429588.1 linkuse as main transcript	n.54-18618G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000178

AC:

AN:

224682

Hom.:

AF XY:

0.0000245

AC XY:

AN XY:

122252

show subpopulations

Gnomad AFR exome

AF:

0.0000721

Gnomad AMR exome

AF:

0.00

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:

0.0000301

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000131

AC:

AN:

1449674

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

720278

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000257

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000136

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000722

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 15, 2014

The Pro28Leu variant in CLDN14 has not been previously reported in individuals w ith hearing loss or in large population studies. Computational prediction tools and conservation analyses suggest that the Pro28Leu variant may impact the prot ein, though this information is not predictive enough to determine pathogenicity . In summary, additional information is needed to fully assess the clinical sign ificance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;D;D;D;D

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.93

D;D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.0

H;H;H;H;H

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-9.7

D;D;D;D;D

REVEL

Pathogenic

0.82

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

0.99

MutPred

0.69

Loss of glycosylation at T25 (P = 0.0601);Loss of glycosylation at T25 (P = 0.0601);Loss of glycosylation at T25 (P = 0.0601);Loss of glycosylation at T25 (P = 0.0601);Loss of glycosylation at T25 (P = 0.0601);

MVP

0.95

MPC

0.96

ClinPred

1.0

GERP RS

4.4

Varity_R

0.97

gMVP

0.82

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