rs113350364

Positions:

• chr21-36461396-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001146079.2(CLDN14):​c.300C>T​(p.Ile100=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,192 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (34 hom.)
• Consequence: CLDN14 NM_001146079.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.35

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=-0.85).
• BP6: Variant 21-36461396-G-A is Benign according to our data. Variant chr21-36461396-G-A is described in ClinVar as [Benign]. Clinvar id is 178603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.35 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00189 (288/152356) while in subpopulation SAS AF= 0.0159 (77/4828). AF 95% confidence interval is 0.0131. There are 1 homozygotes in gnomad4. There are 178 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLDN14	NM_001146079.2	c.300C>T	p.Ile100=	synonymous_variant	2/2	ENST00000399135.6
CLDN14-AS1	NR_183529.1	n.468+15389G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLDN14	ENST00000399135.6	c.300C>T	p.Ile100=	synonymous_variant	2/2	1	NM_001146079.2	P1
CLDN14-AS1	ENST00000428667.1	n.277+15389G>A		intron_variant, non_coding_transcript_variant		5
LNCTSI	ENST00000429588.1	n.54-18835G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 280 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00347 AC: 860 AN: 247656 Hom.: 13 AF XY: 0.00412 AC XY: 553 AN XY: 134208

Gnomad AFR exome AF: 0.00205

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.0165

Gnomad EAS exome AF: 0.000818

Gnomad SAS exome AF: 0.0162

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000460

Gnomad OTH exome AF: 0.00395

GnomAD4 exome AF: 0.00173 AC: 2525 AN: 1460836 Hom.: 34 Cov.: 34 AF XY: 0.00218 AC XY: 1584 AN XY: 726756

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.0155

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0144

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000353

Gnomad4 OTH exome AF: 0.00429

GnomAD4 genome AF: 0.00189 AC: 288 AN: 152356 Hom.: 1 Cov.: 33 AF XY: 0.00239 AC XY: 178 AN XY: 74510

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0159

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00231 Hom.: 0

Bravo AF: 0.00192

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000948

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2019	This variant is associated with the following publications: (PMID: 15880785, 23590985) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 15, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 21, 2016	p.Ile100Ile in Exon 03 of CLDN14: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 1.6% (267/16490) o f South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs113350364). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 11, 2016	- -

Autosomal recessive nonsyndromic hearing loss 29 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 25, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.2
DANN	Benign	0.86

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: rs113350364; hg19: chr21-37833694; COSMIC: COSV59771536; COSMIC: COSV59771536;