NM_001146079.2:c.*214dupA

Variant names:

• chr21-36460761-A-AT
• rs547523762
• NM_001146079.2:c.*214dupA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001146079.2(CLDN14):​c.*214dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00788 in 523,788 control chromosomes in the GnomAD database, including 15 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0094 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (1 hom.)
• Consequence: CLDN14 NM_001146079.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.86
• 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 -10 ACMG points.

• BP6: Variant 21-36460761-A-AT is Benign according to our data. Variant chr21-36460761-A-AT is described in ClinVar as Likely_benign. ClinVar VariationId is 1189276.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0094 (1419/150968) while in subpopulation AFR AF = 0.0285 (1174/41164). AF 95% confidence interval is 0.0272. There are 14 homozygotes in GnomAd4. There are 649 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

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.*214dupA		3_prime_UTR	Exon 2 of 2	NP_001139551.1	O95500
	CLDN14	NM_001146077.2		c.*214dupA		3_prime_UTR	Exon 3 of 3	NP_001139549.1	O95500
	CLDN14	NM_001146078.3		c.*214dupA		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.*214dupA		3_prime_UTR	Exon 2 of 2	ENSP00000382087.1	O95500
	CLDN14	ENST00000342108.2	TSL:1	c.*214dupA		3_prime_UTR	Exon 3 of 3	ENSP00000339292.2	O95500
	CLDN14	ENST00000399136.5	TSL:1	c.*214dupA		3_prime_UTR	Exon 3 of 3	ENSP00000382088.1	O95500

Frequencies

GnomAD3 genomes AF: 0.00935 AC: 1410 AN: 150852 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00450

Gnomad ASJ AF: 0.00462

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.000838

Gnomad FIN AF: 0.000871

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.00917

GnomAD4 exome AF: 0.00726 AC: 2707 AN: 372820 Hom.: 1 Cov.: 4 AF XY: 0.00712 AC XY: 1379 AN XY: 193650

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0335 AC: 360 AN: 10754

American (AMR) AF: 0.00704 AC: 107 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00657 AC: 76 AN: 11566

East Asian (EAS) AF: 0.00590 AC: 156 AN: 26442

South Asian (SAS) AF: 0.00641 AC: 212 AN: 33098

European-Finnish (FIN) AF: 0.00492 AC: 121 AN: 24610

Middle Eastern (MID) AF: 0.0109 AC: 18 AN: 1654

European-Non Finnish (NFE) AF: 0.00648 AC: 1474 AN: 227586

Other (OTH) AF: 0.00835 AC: 183 AN: 21920

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00940 AC: 1419 AN: 150968 Hom.: 14 Cov.: 32 AF XY: 0.00880 AC XY: 649 AN XY: 73778

African (AFR) AF: 0.0285 AC: 1174 AN: 41164

American (AMR) AF: 0.00449 AC: 68 AN: 15140

Ashkenazi Jewish (ASJ) AF: 0.00462 AC: 16 AN: 3462

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5152

South Asian (SAS) AF: 0.000838 AC: 4 AN: 4772

European-Finnish (FIN) AF: 0.000871 AC: 9 AN: 10336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00182 AC: 123 AN: 67648

Other (OTH) AF: 0.00907 AC: 19 AN: 2094

Alfa AF: 0.000930 Hom.: 0

Bravo AF: 0.0103

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.9
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: rs547523762; hg19: chr21-37833059;