rs219742

Variant names:

• chr21-36479703-T-C
• rs219742
• NM_001146079.2:c.-290A>G

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.-290A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 152,126 control chromosomes in the GnomAD database, including 10,182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (10180 hom., cov: 32)
  • Exomes 𝑓: 0.32 (2 hom.)
• Consequence: CLDN14 NM_001146079.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.13
• 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=-0.91).
• BP6: Variant 21-36479703-T-C is Benign according to our data. Variant chr21-36479703-T-C is described in ClinVar as Benign. ClinVar VariationId is 339902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.57 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN14	NM_001146079.2	MANE Select	c.-290A>G		5_prime_UTR	Exon 1 of 2	NP_001139551.1
	CLDN14	NM_144492.3		c.-480A>G		5_prime_UTR	Exon 1 of 3	NP_652763.1
	CLDN14	NM_001146077.2		c.-81-17927A>G		intron	N/A	NP_001139549.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN14	ENST00000399135.6	TSL:1 MANE Select	c.-290A>G		5_prime_UTR	Exon 1 of 2	ENSP00000382087.1
	CLDN14	ENST00000399137.5	TSL:1	c.-480A>G		5_prime_UTR	Exon 1 of 3	ENSP00000382090.1
	CLDN14	ENST00000342108.2	TSL:1	c.-81-17927A>G		intron	N/A	ENSP00000339292.2

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50380 AN: 151974 Hom.: 10157 Cov.: 32

Gnomad AFR AF: 0.576

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.307

GnomAD4 exome AF: 0.324 AC: 11 AN: 34 Hom.: 2 Cov.: 0 AF XY: 0.308 AC XY: 8 AN XY: 26

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.333 AC: 8 AN: 24

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.332 AC: 50456 AN: 152092 Hom.: 10180 Cov.: 32 AF XY: 0.325 AC XY: 24190 AN XY: 74366

African (AFR) AF: 0.576 AC: 23897 AN: 41472

American (AMR) AF: 0.272 AC: 4152 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 899 AN: 3472

East Asian (EAS) AF: 0.122 AC: 633 AN: 5172

South Asian (SAS) AF: 0.283 AC: 1363 AN: 4820

European-Finnish (FIN) AF: 0.219 AC: 2322 AN: 10592

Middle Eastern (MID) AF: 0.219 AC: 64 AN: 292

European-Non Finnish (NFE) AF: 0.237 AC: 16095 AN: 67976

Other (OTH) AF: 0.309 AC: 653 AN: 2116

Alfa AF: 0.296 Hom.: 2830

Bravo AF: 0.346

Asia WGS AF: 0.248 AC: 865 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.17
DANN	Benign	0.45
PhyloP100		-2.1
PromoterAI		0.056	Neutral
Mutation Taster		=300/0	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: rs219742; hg19: chr21-37852001;