NM_001146079.2:c.63G>A

Variant names:

• chr21-36461633-C-T
• rs117560775
• NM_001146079.2:c.63G>A

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.63G>A​(p.Thr21Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 1,585,838 control chromosomes in the GnomAD database, including 849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (75 hom., cov: 33)
  • Exomes 𝑓: 0.029 (774 hom.)
• Consequence: CLDN14 NM_001146079.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.64
• Publications: 5 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=-0.62).
• BP6: Variant 21-36461633-C-T is Benign according to our data. Variant chr21-36461633-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0636 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.63G>A	p.Thr21Thr	synonymous	Exon 2 of 2	NP_001139551.1	O95500
	CLDN14	NM_001146077.2		c.63G>A	p.Thr21Thr	synonymous	Exon 3 of 3	NP_001139549.1	O95500
	CLDN14	NM_001146078.3		c.63G>A	p.Thr21Thr	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.63G>A	p.Thr21Thr	synonymous	Exon 2 of 2	ENSP00000382087.1	O95500
	CLDN14	ENST00000342108.2	TSL:1	c.63G>A	p.Thr21Thr	synonymous	Exon 3 of 3	ENSP00000339292.2	O95500
	CLDN14	ENST00000399136.5	TSL:1	c.63G>A	p.Thr21Thr	synonymous	Exon 3 of 3	ENSP00000382088.1	O95500

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3540 AN: 152084 Hom.: 74 Cov.: 33

Gnomad AFR AF: 0.00548

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0671

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.00651

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0284

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0303 AC: 5988 AN: 197896 AF XY: 0.0293

Gnomad AFR exome AF: 0.00621

Gnomad AMR exome AF: 0.0833

Gnomad ASJ exome AF: 0.0286

Gnomad EAS exome AF: 0.0000706

Gnomad FIN exome AF: 0.00659

Gnomad NFE exome AF: 0.0280

Gnomad OTH exome AF: 0.0324

GnomAD4 exome AF: 0.0290 AC: 41546 AN: 1433636 Hom.: 774 Cov.: 33 AF XY: 0.0287 AC XY: 20407 AN XY: 711016

African (AFR) AF: 0.00522 AC: 171 AN: 32752

American (AMR) AF: 0.0802 AC: 3215 AN: 40104

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 796 AN: 25596

East Asian (EAS) AF: 0.0000792 AC: 3 AN: 37858

South Asian (SAS) AF: 0.0235 AC: 1947 AN: 82722

European-Finnish (FIN) AF: 0.00832 AC: 421 AN: 50600

Middle Eastern (MID) AF: 0.0360 AC: 206 AN: 5722

European-Non Finnish (NFE) AF: 0.0302 AC: 33160 AN: 1098886

Other (OTH) AF: 0.0274 AC: 1627 AN: 59396

GnomAD4 genome AF: 0.0233 AC: 3541 AN: 152202 Hom.: 75 Cov.: 33 AF XY: 0.0228 AC XY: 1697 AN XY: 74400

African (AFR) AF: 0.00551 AC: 229 AN: 41532

American (AMR) AF: 0.0671 AC: 1026 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 120 AN: 3468

East Asian (EAS) AF: 0.000968 AC: 5 AN: 5164

South Asian (SAS) AF: 0.0205 AC: 99 AN: 4828

European-Finnish (FIN) AF: 0.00651 AC: 69 AN: 10604

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0284 AC: 1932 AN: 67986

Other (OTH) AF: 0.0256 AC: 54 AN: 2112

Alfa AF: 0.0250 Hom.: 23

Bravo AF: 0.0262

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Autosomal recessive nonsyndromic hearing loss 29 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	6.5
DANN	Benign	0.84
PhyloP100		-1.6
Mutation Taster		=98/2	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: rs117560775; hg19: chr21-37833931; COSMIC: COSV59774438; COSMIC: COSV59774438;