rs398591

Positions:

• chr21-36548471-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000342108.2(CLDN14):​c.-220+27940C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.832 in 152,130 control chromosomes in the GnomAD database, including 53,176 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.

• Frequency: Genomes: 𝑓 0.83 (53176 hom., cov: 32)
• Consequence: CLDN14 ENST00000342108.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.344

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLDN14	NM_001146077.2	c.-220+27940C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLDN14	ENST00000342108.2	c.-220+27940C>T		intron_variant		1		P1

Frequencies

GnomAD3 genomes AF: 0.832 AC: 126522 AN: 152012 Hom.: 53159 Cov.: 32

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.928

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.923

Gnomad EAS AF: 0.662

Gnomad SAS AF: 0.815

Gnomad FIN AF: 0.773

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.899

Gnomad OTH AF: 0.845

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.832 AC: 126592 AN: 152130 Hom.: 53176 Cov.: 32 AF XY: 0.823 AC XY: 61207 AN XY: 74364

Gnomad4 AFR AF: 0.783

Gnomad4 AMR AF: 0.744

Gnomad4 ASJ AF: 0.923

Gnomad4 EAS AF: 0.662

Gnomad4 SAS AF: 0.815

Gnomad4 FIN AF: 0.773

Gnomad4 NFE AF: 0.899

Gnomad4 OTH AF: 0.846

Alfa AF: 0.841 Hom.: 8521

Bravo AF: 0.825

Asia WGS AF: 0.720 AC: 2507 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.68
DANN	Benign	0.44

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs398591; hg19: chr21-37920769;