chr21-36461036-A-T

Position:

• chr21-36461036-A-T

Variant summary

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

The NM_001146079.2(CLDN14):​c.660T>A​(p.Asn220Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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: 1.38

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:):

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=0.33385155).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLDN14	NM_001146079.2	c.660T>A	p.Asn220Lys	missense_variant	2/2	ENST00000399135.6	NP_001139551.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLDN14	ENST00000399135.6	c.660T>A	p.Asn220Lys	missense_variant	2/2	1	NM_001146079.2	ENSP00000382087.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

GeneDx

Jun 18, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.065	T;T;T;T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.73	.;.;.;.;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.33	T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.0	N;N;N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.95	N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.16	T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T
Polyphen		0.80	P;P;P;P;P
Vest4		0.48
MutPred		0.38		Gain of ubiquitination at N220 (P = 0.0121);Gain of ubiquitination at N220 (P = 0.0121);Gain of ubiquitination at N220 (P = 0.0121);Gain of ubiquitination at N220 (P = 0.0121);Gain of ubiquitination at N220 (P = 0.0121);
MVP		0.75
MPC		0.73
ClinPred		0.81	D
GERP RS		2.4
Varity_R		0.087
gMVP		0.71

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

LitVar

Other links and lift over

dbSNP: rs1477443355; hg19: chr21-37833334;