chr21-36460869-C-T

Variant names:

• chr21-36460869-C-T
• rs112112443
• NM_001146079.2:c.*107G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001146079.2(CLDN14):​c.*107G>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 0.000937 in 1,343,872 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (5 hom.)
• Consequence: CLDN14 NM_001146079.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.175
• Publications: 1 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=-0.8).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00106 (161/152222) while in subpopulation AMR AF = 0.00275 (42/15290). AF 95% confidence interval is 0.00209. There are 2 homozygotes in GnomAd4. There are 78 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 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.*107G>A		3_prime_UTR	Exon 2 of 2	NP_001139551.1	O95500
	CLDN14	NM_001146077.2		c.*107G>A		3_prime_UTR	Exon 3 of 3	NP_001139549.1	O95500
	CLDN14	NM_001146078.3		c.*107G>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.*107G>A		3_prime_UTR	Exon 2 of 2	ENSP00000382087.1	O95500
	CLDN14	ENST00000342108.2	TSL:1	c.*107G>A		3_prime_UTR	Exon 3 of 3	ENSP00000339292.2	O95500
	CLDN14	ENST00000399136.5	TSL:1	c.*107G>A		3_prime_UTR	Exon 3 of 3	ENSP00000382088.1	O95500

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152104 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.000921 AC: 1098 AN: 1191650 Hom.: 5 Cov.: 16 AF XY: 0.000957 AC XY: 565 AN XY: 590420

African (AFR) AF: 0.000762 AC: 21 AN: 27558

American (AMR) AF: 0.00262 AC: 89 AN: 33990

Ashkenazi Jewish (ASJ) AF: 0.0131 AC: 303 AN: 23098

East Asian (EAS) AF: 0.00 AC: 0 AN: 34388

South Asian (SAS) AF: 0.000423 AC: 31 AN: 73340

European-Finnish (FIN) AF: 0.0000222 AC: 1 AN: 45058

Middle Eastern (MID) AF: 0.00849 AC: 31 AN: 3650

European-Non Finnish (NFE) AF: 0.000567 AC: 510 AN: 899794

Other (OTH) AF: 0.00221 AC: 112 AN: 50774

GnomAD4 genome AF: 0.00106 AC: 161 AN: 152222 Hom.: 2 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74422

African (AFR) AF: 0.000265 AC: 11 AN: 41532

American (AMR) AF: 0.00275 AC: 42 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000764 AC: 52 AN: 68024

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00125 Hom.: 0

Bravo AF: 0.00139

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	-0.80
CADD	Benign	1.9
DANN	Benign	0.81
PhyloP100		-0.17
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: rs112112443; hg19: chr21-37833167;