rs219779

Variant names:

• chr21-36461453-G-A
• rs219779
• NM_001146079.2:c.243C>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.243C>T​(p.Arg81Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,613,114 control chromosomes in the GnomAD database, including 50,317 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5073 hom., cov: 33)
  • Exomes 𝑓: 0.24 (45244 hom.)
• Consequence: CLDN14 NM_001146079.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.13
• Publications: 31 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=-0.81).
• BP6: Variant 21-36461453-G-A is Benign according to our data. Variant chr21-36461453-G-A is described in ClinVar as Benign. ClinVar VariationId is 44084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 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.243C>T	p.Arg81Arg	synonymous	Exon 2 of 2	NP_001139551.1	O95500
	CLDN14	NM_001146077.2		c.243C>T	p.Arg81Arg	synonymous	Exon 3 of 3	NP_001139549.1	O95500
	CLDN14	NM_001146078.3		c.243C>T	p.Arg81Arg	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.243C>T	p.Arg81Arg	synonymous	Exon 2 of 2	ENSP00000382087.1	O95500
	CLDN14	ENST00000342108.2	TSL:1	c.243C>T	p.Arg81Arg	synonymous	Exon 3 of 3	ENSP00000339292.2	O95500
	CLDN14	ENST00000399136.5	TSL:1	c.243C>T	p.Arg81Arg	synonymous	Exon 3 of 3	ENSP00000382088.1	O95500

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37944 AN: 152062 Hom.: 5055 Cov.: 33

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.00771

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.260

GnomAD2 exomes AF: 0.212 AC: 52925 AN: 249378 AF XY: 0.210

Gnomad AFR exome AF: 0.304

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.00534

Gnomad FIN exome AF: 0.206

Gnomad NFE exome AF: 0.252

Gnomad OTH exome AF: 0.222

GnomAD4 exome AF: 0.242 AC: 354123 AN: 1460934 Hom.: 45244 Cov.: 36 AF XY: 0.239 AC XY: 173901 AN XY: 726808

African (AFR) AF: 0.309 AC: 10351 AN: 33474

American (AMR) AF: 0.197 AC: 8822 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 6172 AN: 26124

East Asian (EAS) AF: 0.00768 AC: 305 AN: 39696

South Asian (SAS) AF: 0.158 AC: 13592 AN: 86258

European-Finnish (FIN) AF: 0.210 AC: 11047 AN: 52552

Middle Eastern (MID) AF: 0.249 AC: 1436 AN: 5768

European-Non Finnish (NFE) AF: 0.259 AC: 288181 AN: 1111954

Other (OTH) AF: 0.235 AC: 14217 AN: 60388

GnomAD4 genome AF: 0.250 AC: 38010 AN: 152180 Hom.: 5073 Cov.: 33 AF XY: 0.243 AC XY: 18076 AN XY: 74416

African (AFR) AF: 0.310 AC: 12893 AN: 41524

American (AMR) AF: 0.228 AC: 3488 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 818 AN: 3472

East Asian (EAS) AF: 0.00773 AC: 40 AN: 5176

South Asian (SAS) AF: 0.148 AC: 714 AN: 4828

European-Finnish (FIN) AF: 0.211 AC: 2238 AN: 10598

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

European-Non Finnish (NFE) AF: 0.251 AC: 17065 AN: 67982

Other (OTH) AF: 0.258 AC: 543 AN: 2108

Alfa AF: 0.254 Hom.: 3933

Bravo AF: 0.251

Asia WGS AF: 0.109 AC: 382 AN: 3478

EpiCase AF: 0.251

EpiControl AF: 0.251

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	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	-0.81
CADD	Benign	6.2
DANN	Benign	0.88
PhyloP100		-1.1
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: rs219779; hg19: chr21-37833751; COSMIC: COSV59771947; COSMIC: COSV59771947;