NM_001146079.2:c.*48G>A

Variant names:

• chr21-36460928-C-T
• rs199523516
• NM_001146079.2:c.*48G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001146079.2(CLDN14):​c.*48G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,594,004 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: CLDN14 NM_001146079.2 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -3.37
• Publications: 0 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 21-36460928-C-T is Benign according to our data. Variant chr21-36460928-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 895962.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00143 (218/152294) while in subpopulation AFR AF = 0.00452 (188/41562). AF 95% confidence interval is 0.00399. There are 0 homozygotes in GnomAd4. There are 91 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.*48G>A		3_prime_UTR	Exon 2 of 2	NP_001139551.1	O95500
	CLDN14	NM_001146077.2		c.*48G>A		3_prime_UTR	Exon 3 of 3	NP_001139549.1	O95500
	CLDN14	NM_001146078.3		c.*48G>A		3_prime_UTR	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.*48G>A		3_prime_UTR	Exon 2 of 2	ENSP00000382087.1	O95500
	CLDN14	ENST00000342108.2	TSL:1	c.*48G>A		3_prime_UTR	Exon 3 of 3	ENSP00000339292.2	O95500
	CLDN14	ENST00000399136.5	TSL:1	c.*48G>A		3_prime_UTR	Exon 3 of 3	ENSP00000382088.1	O95500

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00454

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000615 AC: 138 AN: 224220 AF XY: 0.000484

Gnomad AFR exome AF: 0.00471

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000201

Gnomad OTH exome AF: 0.000358

GnomAD4 exome AF: 0.000214 AC: 309 AN: 1441710 Hom.: 1 Cov.: 30 AF XY: 0.000193 AC XY: 138 AN XY: 715074

African (AFR) AF: 0.00523 AC: 173 AN: 33086

American (AMR) AF: 0.00210 AC: 88 AN: 41858

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25820

East Asian (EAS) AF: 0.00 AC: 0 AN: 38944

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52448

Middle Eastern (MID) AF: 0.000241 AC: 1 AN: 4146

European-Non Finnish (NFE) AF: 0.0000245 AC: 27 AN: 1101670

Other (OTH) AF: 0.000320 AC: 19 AN: 59392

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.00122 AC XY: 91 AN XY: 74484

African (AFR) AF: 0.00452 AC: 188 AN: 41562

American (AMR) AF: 0.00150 AC: 23 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000470 Hom.: 0

Bravo AF: 0.00178

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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	-0.86
CADD	Benign	0.39
DANN	Benign	0.61
PhyloP100		-3.4
Mutation Taster		=100/0	polymorphism

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: rs199523516; hg19: chr21-37833226;