21-36461009-C-T

Variant names:

• chr21-36461009-C-T
• rs219780
• NM_001146079.2:c.687G>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.687G>A​(p.Thr229Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,612,880 control chromosomes in the GnomAD database, including 32,630 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3182 hom., cov: 32)
  • Exomes 𝑓: 0.19 (29448 hom.)
• Consequence: CLDN14 NM_001146079.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.16
• Publications: 53 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=-0.84).
• BP6: Variant 21-36461009-C-T is Benign according to our data. Variant chr21-36461009-C-T is described in ClinVar as Benign. ClinVar VariationId is 44088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.238 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.687G>A	p.Thr229Thr	synonymous	Exon 2 of 2	NP_001139551.1	O95500
	CLDN14	NM_001146077.2		c.687G>A	p.Thr229Thr	synonymous	Exon 3 of 3	NP_001139549.1	O95500
	CLDN14	NM_001146078.3		c.687G>A	p.Thr229Thr	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.687G>A	p.Thr229Thr	synonymous	Exon 2 of 2	ENSP00000382087.1	O95500
	CLDN14	ENST00000342108.2	TSL:1	c.687G>A	p.Thr229Thr	synonymous	Exon 3 of 3	ENSP00000339292.2	O95500
	CLDN14	ENST00000399136.5	TSL:1	c.687G>A	p.Thr229Thr	synonymous	Exon 3 of 3	ENSP00000382088.1	O95500

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29802 AN: 152002 Hom.: 3175 Cov.: 32

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0981

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.205

GnomAD2 exomes AF: 0.163 AC: 40650 AN: 250066 AF XY: 0.161

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.0960

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.000980

Gnomad FIN exome AF: 0.195

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.194 AC: 284010 AN: 1460760 Hom.: 29448 Cov.: 34 AF XY: 0.191 AC XY: 139110 AN XY: 726670

African (AFR) AF: 0.242 AC: 8105 AN: 33458

American (AMR) AF: 0.100 AC: 4469 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 5032 AN: 26136

East Asian (EAS) AF: 0.000806 AC: 32 AN: 39694

South Asian (SAS) AF: 0.104 AC: 8964 AN: 86214

European-Finnish (FIN) AF: 0.196 AC: 10464 AN: 53402

Middle Eastern (MID) AF: 0.161 AC: 817 AN: 5074

European-Non Finnish (NFE) AF: 0.212 AC: 235258 AN: 1111792

Other (OTH) AF: 0.180 AC: 10869 AN: 60286

GnomAD4 genome AF: 0.196 AC: 29849 AN: 152120 Hom.: 3182 Cov.: 32 AF XY: 0.191 AC XY: 14219 AN XY: 74368

African (AFR) AF: 0.242 AC: 10039 AN: 41498

American (AMR) AF: 0.136 AC: 2085 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 649 AN: 3468

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5170

South Asian (SAS) AF: 0.0988 AC: 476 AN: 4820

European-Finnish (FIN) AF: 0.200 AC: 2119 AN: 10586

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.204 AC: 13874 AN: 67968

Other (OTH) AF: 0.204 AC: 430 AN: 2112

Alfa AF: 0.202 Hom.: 8269

Bravo AF: 0.193

Asia WGS AF: 0.0780 AC: 274 AN: 3478

EpiCase AF: 0.203

EpiControl AF: 0.199

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Autosomal recessive nonsyndromic hearing loss 29 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.73
DANN	Benign	0.77
PhyloP100		-1.2
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: rs219780; hg19: chr21-37833307; COSMIC: COSV59778658; COSMIC: COSV59778658;