rs61745291

Variant names:

• chr21-36461063-G-A
• rs61745291
• NM_001146079.2:c.633C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001146079.2(CLDN14):​c.633C>T​(p.Tyr211Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00367 in 1,614,066 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (111 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (95 hom.)
• Consequence: CLDN14 NM_001146079.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.79
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 21-36461063-G-A is Benign according to our data. Variant chr21-36461063-G-A is described in ClinVar as Benign. ClinVar VariationId is 44086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.8 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0608 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.633C>T	p.Tyr211Tyr	synonymous	Exon 2 of 2	NP_001139551.1	O95500
	CLDN14	NM_001146077.2		c.633C>T	p.Tyr211Tyr	synonymous	Exon 3 of 3	NP_001139549.1	O95500
	CLDN14	NM_001146078.3		c.633C>T	p.Tyr211Tyr	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.633C>T	p.Tyr211Tyr	synonymous	Exon 2 of 2	ENSP00000382087.1	O95500
	CLDN14	ENST00000342108.2	TSL:1	c.633C>T	p.Tyr211Tyr	synonymous	Exon 3 of 3	ENSP00000339292.2	O95500
	CLDN14	ENST00000399136.5	TSL:1	c.633C>T	p.Tyr211Tyr	synonymous	Exon 3 of 3	ENSP00000382088.1	O95500

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2785 AN: 152224 Hom.: 110 Cov.: 33

Gnomad AFR AF: 0.0628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00850

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.00509 AC: 1277 AN: 250906 AF XY: 0.00401

Gnomad AFR exome AF: 0.0672

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00214 AC: 3128 AN: 1461722 Hom.: 95 Cov.: 34 AF XY: 0.00191 AC XY: 1390 AN XY: 727138

African (AFR) AF: 0.0704 AC: 2357 AN: 33480

American (AMR) AF: 0.00382 AC: 171 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000957 AC: 25 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00650 AC: 37 AN: 5696

European-Non Finnish (NFE) AF: 0.000202 AC: 225 AN: 1111960

Other (OTH) AF: 0.00482 AC: 291 AN: 60360

GnomAD4 genome AF: 0.0183 AC: 2792 AN: 152344 Hom.: 111 Cov.: 33 AF XY: 0.0182 AC XY: 1356 AN XY: 74496

African (AFR) AF: 0.0628 AC: 2611 AN: 41566

American (AMR) AF: 0.00849 AC: 130 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68046

Other (OTH) AF: 0.0142 AC: 30 AN: 2116

Alfa AF: 0.00982 Hom.: 33

Bravo AF: 0.0212

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 29 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.5
DANN	Benign	0.71
PhyloP100		2.8
Mutation Taster		=78/22	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: rs61745291; hg19: chr21-37833361;