rs219777

Variant names:

• chr21-36462423-G-A
• rs219777
• NM_001146079.2:c.-81-647C>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.-81-647C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 151,856 control chromosomes in the GnomAD database, including 4,799 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 0.24 (4799 hom., cov: 31)
• Consequence: CLDN14 NM_001146079.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.88
• 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: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146079.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN14	NM_001146079.2	MANE Select	c.-81-647C>T		intron	N/A	NP_001139551.1	O95500
	CLDN14	NM_001146077.2		c.-81-647C>T		intron	N/A	NP_001139549.1	O95500
	CLDN14	NM_001146078.3		c.-81-647C>T		intron	N/A	NP_001139550.1	O95500

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN14	ENST00000399135.6	TSL:1 MANE Select	c.-81-647C>T		intron	N/A	ENSP00000382087.1	O95500
	CLDN14	ENST00000342108.2	TSL:1	c.-81-647C>T		intron	N/A	ENSP00000339292.2	O95500
	CLDN14	ENST00000399136.5	TSL:1	c.-81-647C>T		intron	N/A	ENSP00000382088.1	O95500

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36512 AN: 151736 Hom.: 4783 Cov.: 31

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.247

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

GnomAD4 genome AF: 0.241 AC: 36576 AN: 151856 Hom.: 4799 Cov.: 31 AF XY: 0.234 AC XY: 17409 AN XY: 74244

African (AFR) AF: 0.320 AC: 13221 AN: 41348

American (AMR) AF: 0.216 AC: 3294 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 787 AN: 3470

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5162

South Asian (SAS) AF: 0.118 AC: 568 AN: 4818

European-Finnish (FIN) AF: 0.206 AC: 2180 AN: 10562

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15822 AN: 67932

Other (OTH) AF: 0.245 AC: 515 AN: 2106

Alfa AF: 0.269 Hom.: 1324

Bravo AF: 0.244

Asia WGS AF: 0.0910 AC: 319 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.26
DANN	Benign	0.57
PhyloP100		-3.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs219777; hg19: chr21-37834721; COSMIC: COSV59777720; COSMIC: COSV59777720;