rs139628442

Positions:

• chr21-36460966-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001146079.2(CLDN14):​c.*10G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,611,408 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (14 hom.)
• Consequence: CLDN14 NM_001146079.2 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.396

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 21-36460966-C-G is Benign according to our data. Variant chr21-36460966-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196574.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0032 (487/152348) while in subpopulation NFE AF= 0.00491 (334/68034). AF 95% confidence interval is 0.00448. There are 1 homozygotes in gnomad4. There are 234 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLDN14	NM_001146079.2	c.*10G>C		3_prime_UTR_variant	2/2	ENST00000399135.6
CLDN14-AS1	NR_183529.1	n.468+14959C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLDN14	ENST00000399135.6	c.*10G>C		3_prime_UTR_variant	2/2	1	NM_001146079.2	P1
CLDN14-AS1	ENST00000428667.1	n.277+14959C>G		intron_variant, non_coding_transcript_variant		5
LNCTSI	ENST00000429588.1	n.54-19265C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00320 AC: 487 AN: 152230 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00696

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00491

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00294 AC: 725 AN: 246742 Hom.: 3 AF XY: 0.00281 AC XY: 377 AN XY: 133932

Gnomad AFR exome AF: 0.000628

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000657

Gnomad FIN exome AF: 0.00712

Gnomad NFE exome AF: 0.00445

Gnomad OTH exome AF: 0.00250

GnomAD4 exome AF: 0.00394 AC: 5754 AN: 1459060 Hom.: 14 Cov.: 30 AF XY: 0.00395 AC XY: 2868 AN XY: 725686

Gnomad4 AFR exome AF: 0.000479

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.00598

Gnomad4 NFE exome AF: 0.00461

Gnomad4 OTH exome AF: 0.00342

GnomAD4 genome AF: 0.00320 AC: 487 AN: 152348 Hom.: 1 Cov.: 33 AF XY: 0.00314 AC XY: 234 AN XY: 74496

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00696

Gnomad4 NFE AF: 0.00491

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00348 Hom.: 2

Bravo AF: 0.00260

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	*10G>C in Exon 03 of CLDN14: This variant is not expected to have clinical signi ficance because it has been identified in 0.4% (25/7020) of European American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs139628442). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 06, 2015	- -

Autosomal recessive nonsyndromic hearing loss 29 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 25, 2019

- -

CLDN14-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.2
DANN	Benign	0.75

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: rs139628442; hg19: chr21-37833264;