chr21-36460988-G-A

Variant names:

• chr21-36460988-G-A
• rs774161015
• NM_001146079.2:c.708C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001146079.2(CLDN14):​c.708C>T​(p.Asn236Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,612,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: CLDN14 NM_001146079.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.284
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 21-36460988-G-A is Benign according to our data. Variant chr21-36460988-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3606084.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.284 with no splicing effect.

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.708C>T	p.Asn236Asn	synonymous	Exon 2 of 2	NP_001139551.1	O95500
	CLDN14	NM_001146077.2		c.708C>T	p.Asn236Asn	synonymous	Exon 3 of 3	NP_001139549.1	O95500
	CLDN14	NM_001146078.3		c.708C>T	p.Asn236Asn	synonymous	Exon 3 of 3	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.708C>T	p.Asn236Asn	synonymous	Exon 2 of 2	ENSP00000382087.1	O95500
	CLDN14	ENST00000342108.2	TSL:1	c.708C>T	p.Asn236Asn	synonymous	Exon 3 of 3	ENSP00000339292.2	O95500
	CLDN14	ENST00000399136.5	TSL:1	c.708C>T	p.Asn236Asn	synonymous	Exon 3 of 3	ENSP00000382088.1	O95500

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249412 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1460388 Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13 AN XY: 726464

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.000157 AC: 7 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4724

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1111846

Other (OTH) AF: 0.00 AC: 0 AN: 60244

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.000262 AC: 4 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000491

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.1
DANN	Benign	0.84
PhyloP100		0.28

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: rs774161015; hg19: chr21-37833286;