21-36460761-A-AT

Position:

• chr21-36460761-A-AT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001146079.2(CLDN14):​c.*214_*215insA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00788 in 523,788 control chromosomes in the GnomAD database, including 15 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0094 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (1 hom.)
• Consequence: CLDN14 NM_001146079.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.86

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 -10 ACMG points.

• BP6: Variant 21-36460761-A-AT is Benign according to our data. Variant chr21-36460761-A-AT is described in ClinVar as [Likely_benign]. Clinvar id is 1189276.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0094 (1419/150968) while in subpopulation AFR AF= 0.0285 (1174/41164). AF 95% confidence interval is 0.0272. There are 14 homozygotes in gnomad4. There are 649 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN14	NM_001146079.2	c.*214_*215insA		3_prime_UTR_variant	2/2	ENST00000399135.6	NP_001139551.1
CLDN14-AS1	NR_183529.1	n.468+14764dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLDN14	ENST00000399135.6	c.*214_*215insA		3_prime_UTR_variant	2/2	1	NM_001146079.2	ENSP00000382087	P1
CLDN14-AS1	ENST00000428667.1	n.277+14764dup		intron_variant, non_coding_transcript_variant		5
LNCTSI	ENST00000429588.1	n.54-19460dup		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00935 AC: 1410 AN: 150852 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00450

Gnomad ASJ AF: 0.00462

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.000838

Gnomad FIN AF: 0.000871

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.00917

GnomAD4 exome AF: 0.00726 AC: 2707 AN: 372820 Hom.: 1 Cov.: 4 AF XY: 0.00712 AC XY: 1379 AN XY: 193650

Gnomad4 AFR exome AF: 0.0335

Gnomad4 AMR exome AF: 0.00704

Gnomad4 ASJ exome AF: 0.00657

Gnomad4 EAS exome AF: 0.00590

Gnomad4 SAS exome AF: 0.00641

Gnomad4 FIN exome AF: 0.00492

Gnomad4 NFE exome AF: 0.00648

Gnomad4 OTH exome AF: 0.00835

GnomAD4 genome AF: 0.00940 AC: 1419 AN: 150968 Hom.: 14 Cov.: 32 AF XY: 0.00880 AC XY: 649 AN XY: 73778

Gnomad4 AFR AF: 0.0285

Gnomad4 AMR AF: 0.00449

Gnomad4 ASJ AF: 0.00462

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.000838

Gnomad4 FIN AF: 0.000871

Gnomad4 NFE AF: 0.00182

Gnomad4 OTH AF: 0.00907

Bravo AF: 0.0103

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 13, 2019

- -

Computational scores

Source: dbNSFP v4.3

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: rs547523762; hg19: chr21-37833059;