rs219747

Variant names:

• chr21-36477587-G-A
• rs219747
• NM_001146079.2:c.-82+1908C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001146079.2(CLDN14):​c.-82+1908C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 152,042 control chromosomes in the GnomAD database, including 14,231 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.39 (14231 hom., cov: 32)
  • Exomes 𝑓: 0.13 (0 hom.)
• Consequence: CLDN14 NM_001146079.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.460
• Publications: 7 publications found

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]

LNCTSI (HGNC:56660): (lncRNA TGF-beta/SMAD3 pathway interacting)

CLDN14-AS1 (HGNC:55953): (CLDN14 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN14	NM_001146079.2	c.-82+1908C>T		intron_variant	Intron 1 of 1	ENST00000399135.6	NP_001139551.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN14	ENST00000399135.6	c.-82+1908C>T		intron_variant	Intron 1 of 1	1	NM_001146079.2	ENSP00000382087.1

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59758 AN: 151910 Hom.: 14200 Cov.: 32

Gnomad AFR AF: 0.679

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.289

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.370

GnomAD4 exome AF: 0.125 AC: 2 AN: 16 Hom.: 0 Cov.: 0 AF XY: 0.125 AC XY: 2 AN XY: 16

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0833 AC: 1 AN: 12

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.394 AC: 59839 AN: 152026 Hom.: 14231 Cov.: 32 AF XY: 0.389 AC XY: 28909 AN XY: 74308

African (AFR) AF: 0.679 AC: 28118 AN: 41440

American (AMR) AF: 0.332 AC: 5071 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1025 AN: 3470

East Asian (EAS) AF: 0.290 AC: 1500 AN: 5174

South Asian (SAS) AF: 0.368 AC: 1773 AN: 4818

European-Finnish (FIN) AF: 0.279 AC: 2952 AN: 10568

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.267 AC: 18143 AN: 67972

Other (OTH) AF: 0.371 AC: 783 AN: 2108

Alfa AF: 0.347 Hom.: 1461

Bravo AF: 0.409

Asia WGS AF: 0.376 AC: 1309 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.41
PhyloP100		-0.46
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs219747; hg19: chr21-37849885;