chr21-36460761-A-ATTT

Variant names:

• chr21-36460761-A-ATTT
• rs547523762
• NM_001146079.2:c.*212_*214dupAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001146079.2(CLDN14):​c.*212_*214dupAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000264 in 379,228 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: CLDN14 NM_001146079.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.*212_*214dupAAA		3_prime_UTR	Exon 2 of 2	NP_001139551.1	O95500
	CLDN14	NM_001146077.2		c.*212_*214dupAAA		3_prime_UTR	Exon 3 of 3	NP_001139549.1	O95500
	CLDN14	NM_001146078.3		c.*212_*214dupAAA		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.*212_*214dupAAA		3_prime_UTR	Exon 2 of 2	ENSP00000382087.1	O95500
	CLDN14	ENST00000342108.2	TSL:1	c.*212_*214dupAAA		3_prime_UTR	Exon 3 of 3	ENSP00000339292.2	O95500
	CLDN14	ENST00000399136.5	TSL:1	c.*212_*214dupAAA		3_prime_UTR	Exon 3 of 3	ENSP00000382088.1	O95500

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000264 AC: 1 AN: 379228 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 197064

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

African (AFR) AF: 0.0000914 AC: 1 AN: 10938

American (AMR) AF: 0.00 AC: 0 AN: 15450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11746

East Asian (EAS) AF: 0.00 AC: 0 AN: 26860

South Asian (SAS) AF: 0.00 AC: 0 AN: 33640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1682

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 231602

Other (OTH) AF: 0.00 AC: 0 AN: 22288

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs547523762; hg19: chr21-37833059;