rs219775

Variant names:

• chr21-36462646-A-G
• rs219775
• NM_001146079.2:c.-81-870T>C

Variant summary

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

The NM_001146079.2(CLDN14):​c.-81-870T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 151,934 control chromosomes in the GnomAD database, including 8,310 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 0.30 (8310 hom., cov: 31)
• Consequence: CLDN14 NM_001146079.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.73
• Publications: 3 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.492 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN14	NM_001146079.2	MANE Select	c.-81-870T>C		intron	N/A	NP_001139551.1
	CLDN14	NM_001146077.2		c.-81-870T>C		intron	N/A	NP_001139549.1
	CLDN14	NM_001146078.3		c.-81-870T>C		intron	N/A	NP_001139550.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN14	ENST00000399135.6	TSL:1 MANE Select	c.-81-870T>C		intron	N/A	ENSP00000382087.1
	CLDN14	ENST00000342108.2	TSL:1	c.-81-870T>C		intron	N/A	ENSP00000339292.2
	CLDN14	ENST00000399136.5	TSL:1	c.-81-870T>C		intron	N/A	ENSP00000382088.1

Frequencies

GnomAD3 genomes AF: 0.303 AC: 45976 AN: 151814 Hom.: 8273 Cov.: 31

Gnomad AFR AF: 0.497

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00754

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.307

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

GnomAD4 genome AF: 0.303 AC: 46064 AN: 151934 Hom.: 8310 Cov.: 31 AF XY: 0.295 AC XY: 21876 AN XY: 74250

African (AFR) AF: 0.497 AC: 20583 AN: 41382

American (AMR) AF: 0.250 AC: 3813 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 834 AN: 3470

East Asian (EAS) AF: 0.00756 AC: 39 AN: 5162

South Asian (SAS) AF: 0.147 AC: 708 AN: 4814

European-Finnish (FIN) AF: 0.211 AC: 2231 AN: 10566

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 17004 AN: 67960

Other (OTH) AF: 0.305 AC: 641 AN: 2104

Alfa AF: 0.270 Hom.: 8047

Bravo AF: 0.313

Asia WGS AF: 0.123 AC: 430 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.71
DANN	Benign	0.48
PhyloP100		-1.7
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: rs219775; hg19: chr21-37834944;