21-36461594-C-T

Position:

• chr21-36461594-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_001146079.2(CLDN14):​c.102G>A​(p.Ala34Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000311 in 1,609,096 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: CLDN14 NM_001146079.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.90

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:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 21-36461594-C-T is Benign according to our data. Variant chr21-36461594-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 504558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.9 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN14	NM_001146079.2	c.102G>A	p.Ala34Ala	synonymous_variant	2/2	ENST00000399135.6	NP_001139551.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLDN14	ENST00000399135.6	c.102G>A	p.Ala34Ala	synonymous_variant	2/2	1	NM_001146079.2	ENSP00000382087.1

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152182 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000310 AC: 74 AN: 238480 Hom.: 0 AF XY: 0.000285 AC XY: 37 AN XY: 129646

Gnomad AFR exome AF: 0.000664

Gnomad AMR exome AF: 0.000567

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000170

Gnomad SAS exome AF: 0.000204

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.000851

GnomAD4 exome AF: 0.000290 AC: 422 AN: 1456796 Hom.: 0 Cov.: 33 AF XY: 0.000266 AC XY: 193 AN XY: 724330

Gnomad4 AFR exome AF: 0.000330

Gnomad4 AMR exome AF: 0.000634

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000203

Gnomad4 SAS exome AF: 0.000222

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000302

Gnomad4 OTH exome AF: 0.000299

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152300 Hom.: 1 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74476

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000597

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 10, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	CLDN14: BP4, BP7 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 22, 2016

p.Ala34Ala in exon 3 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 27/77276 of the tota l chromosomes in the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs146395322). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.9
DANN	Benign	0.83

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: rs146395322; hg19: chr21-37833892;