rs188733

Variant names:

• chr21-36479677-C-G
• rs188733
• NM_001146079.2:c.-264G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001146079.2(CLDN14):​c.-264G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 152,130 control chromosomes in the GnomAD database, including 10,934 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (10934 hom., cov: 32)
  • Exomes 𝑓: 0.17 (0 hom.)
• Consequence: CLDN14 NM_001146079.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.730
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 21-36479677-C-G is Benign according to our data. Variant chr21-36479677-C-G is described in ClinVar as [Benign]. Clinvar id is 339901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN14	NM_001146079.2	c.-264G>C		5_prime_UTR_variant	Exon 1 of 2	ENST00000399135.6	NP_001139551.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN14	ENST00000399135.6	c.-264G>C		5_prime_UTR_variant	Exon 1 of 2	1	NM_001146079.2	ENSP00000382087.1

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51673 AN: 152000 Hom.: 10907 Cov.: 32

Gnomad AFR AF: 0.605

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.314

GnomAD4 exome AF: 0.167 AC: 2 AN: 12 Hom.: 0 Cov.: 0 AF XY: 0.200 AC XY: 2 AN XY: 10

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.200 AC: 2 AN: 10

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.340 AC: 51754 AN: 152118 Hom.: 10934 Cov.: 32 AF XY: 0.334 AC XY: 24807 AN XY: 74374

African (AFR) AF: 0.606 AC: 25136 AN: 41510

American (AMR) AF: 0.276 AC: 4210 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 910 AN: 3470

East Asian (EAS) AF: 0.122 AC: 631 AN: 5176

South Asian (SAS) AF: 0.281 AC: 1352 AN: 4818

European-Finnish (FIN) AF: 0.219 AC: 2316 AN: 10578

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16091 AN: 67978

Other (OTH) AF: 0.316 AC: 666 AN: 2110

Alfa AF: 0.294 Hom.: 1022

Bravo AF: 0.356

Asia WGS AF: 0.244 AC: 849 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 29 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.5
DANN	Benign	0.66
PhyloP100		0.73
PromoterAI		-0.011	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs188733; hg19: chr21-37851975;