21-36461043-T-C

Position:

• chr21-36461043-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001146079.2(CLDN14):​c.653A>G​(p.Lys218Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLDN14 NM_001146079.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.27

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]

CLDN14-AS1 (HGNC:55953): (CLDN14 antisense RNA 1)

LNCTSI (HGNC:56660): (lncRNA TGF-beta/SMAD3 pathway interacting)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27023786).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN14	NM_001146079.2	c.653A>G	p.Lys218Arg	missense_variant	2/2	ENST00000399135.6	NP_001139551.1
CLDN14-AS1	NR_183529.1	n.468+15036T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLDN14	ENST00000399135.6	c.653A>G	p.Lys218Arg	missense_variant	2/2	1	NM_001146079.2	ENSP00000382087	P1
CLDN14-AS1	ENST00000428667.1	n.277+15036T>C		intron_variant, non_coding_transcript_variant		5
LNCTSI	ENST00000429588.1	n.54-19188T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2023

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 218 of the CLDN14 protein (p.Lys218Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CLDN14-related conditions. ClinVar contains an entry for this variant (Variation ID: 2044961). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	T;T;T;T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	.;.;.;.;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.0	N;N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.77	N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.067	T;T;T;T;T
Sift4G	Uncertain	0.042	D;D;D;D;D
Polyphen		0.98	D;D;D;D;D
Vest4		0.35
MutPred		0.22		Loss of ubiquitination at K218 (P = 0.0027);Loss of ubiquitination at K218 (P = 0.0027);Loss of ubiquitination at K218 (P = 0.0027);Loss of ubiquitination at K218 (P = 0.0027);Loss of ubiquitination at K218 (P = 0.0027);
MVP		0.91
MPC		0.85
ClinPred		0.84	D
GERP RS		5.7
Varity_R		0.21
gMVP		0.41

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-37833341;