chr21-36460869-C-T

Position:

• chr21-36460869-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001146079.2(CLDN14):​c.*107G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000937 in 1,343,872 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (5 hom.)
• Consequence: CLDN14 NM_001146079.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.175

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00106 (161/152222) while in subpopulation AMR AF= 0.00275 (42/15290). AF 95% confidence interval is 0.00209. There are 2 homozygotes in gnomad4. There are 78 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLDN14	NM_001146079.2	c.*107G>A		3_prime_UTR_variant	2/2	ENST00000399135.6
CLDN14-AS1	NR_183529.1	n.468+14862C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLDN14	ENST00000399135.6	c.*107G>A		3_prime_UTR_variant	2/2	1	NM_001146079.2	P1
CLDN14-AS1	ENST00000428667.1	n.277+14862C>T		intron_variant, non_coding_transcript_variant		5
LNCTSI	ENST00000429588.1	n.54-19362C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152104 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.000921 AC: 1098 AN: 1191650 Hom.: 5 Cov.: 16 AF XY: 0.000957 AC XY: 565 AN XY: 590420

Gnomad4 AFR exome AF: 0.000762

Gnomad4 AMR exome AF: 0.00262

Gnomad4 ASJ exome AF: 0.0131

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000423

Gnomad4 FIN exome AF: 0.0000222

Gnomad4 NFE exome AF: 0.000567

Gnomad4 OTH exome AF: 0.00221

GnomAD4 genome AF: 0.00106 AC: 161 AN: 152222 Hom.: 2 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74422

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000764

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00125 Hom.: 0

Bravo AF: 0.00139

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 29 Uncertain:1

Uncertain significance, 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, 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 Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.9
DANN	Benign	0.81

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: rs112112443; hg19: chr21-37833167;