21-36461009-C-T

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.687G>A(p.Thr229=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.16

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:55953): (CLDN14 antisense RNA 1)

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

ACMG classification

Verdict is Benign. Variant got -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 id is 44088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-36461009-C-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
CLDN14	NM_001146079.2	c.687G>A	p.Thr229=	synonymous_variant	2/2	ENST00000399135.6
CLDN14-AS1	NR_183529.1	n.468+15002C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLDN14	ENST00000399135.6	c.687G>A	p.Thr229=	synonymous_variant	2/2	1	NM_001146079.2	P1
CLDN14-AS1	ENST00000428667.1	n.277+15002C>T		intron_variant, non_coding_transcript_variant		5
LNCTSI	ENST00000429588.1	n.54-19222C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29802 AN: 152002 Hom.: 3175 Cov.: 32

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

GnomAD3 exomes AF: 0.163 AC: 40650 AN: 250066 Hom.: 3852 AF XY: 0.161 AC XY: 21790 AN XY: 135404

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 SAS exome AF: 0.102

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.: 34 AF XY: 0.191 AC XY: 139110 AN XY: 726670

Gnomad4 AFR exome AF: 0.242

Gnomad4 AMR exome AF: 0.100

Gnomad4 ASJ exome AF: 0.193

Gnomad4 EAS exome AF: 0.000806

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.196

Gnomad4 NFE exome AF: 0.212

Gnomad4 OTH exome AF: 0.180

GnomAD4 genome AF: 0.196 AC: 29849 AN: 152120 Hom.: 3182 Cov.: 32 AF XY: 0.191 AC XY: 14219 AN XY: 74368

Gnomad4 AFR AF: 0.242

Gnomad4 AMR AF: 0.136

Gnomad4 ASJ AF: 0.187

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0988

Gnomad4 FIN AF: 0.200

Gnomad4 NFE AF: 0.204

Gnomad4 OTH AF: 0.204

Alfa AF: 0.203 Hom.: 3955

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 11, 2016	- -
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. -

Autosomal recessive nonsyndromic hearing loss 29 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

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	-0.84
Cadd	Benign	0.73
Dann	Benign	0.77

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: rs219780; hg19: chr21-37833307; COSMIC: COSV59778658; COSMIC: COSV59778658;