chr1-16023920-T-A

Position:

• chr1-16023920-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000331433.5(CLCNKA):​c.221T>A​(p.Val74Glu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLCNKA ENST00000331433.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38

Genes affected

CLCNKA (HGNC:2026): (chloride voltage-gated channel Ka) This gene is a member of the CLC family of voltage-gated chloride channels. The encoded protein is predicted to have 12 transmembrane domains, and requires a beta subunit called barttin to form a functional channel. It is thought to function in salt reabsorption in the kidney and potassium recycling in the inner ear. The gene is highly similar to CLCNKB, which is located 10 kb downstream from this gene. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCNKA	NM_004070.4	c.221T>A	p.Val74Glu	missense_variant	3/20	ENST00000331433.5	NP_004061.3
CLCNKA	NM_001042704.2	c.221T>A	p.Val74Glu	missense_variant	3/20		NP_001036169.1
CLCNKA	NM_001257139.2	c.221T>A	p.Val74Glu	missense_variant	3/19		NP_001244068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCNKA	ENST00000331433.5	c.221T>A	p.Val74Glu	missense_variant	3/20	1	NM_004070.4	ENSP00000332771	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2023

The c.221T>A (p.V74E) alteration is located in exon 3 (coding exon 2) of the CLCNKA gene. This alteration results from a T to A substitution at nucleotide position 221, causing the valine (V) at amino acid position 74 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	.;.;D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.7	M;M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.7	D;N;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.020	D;D;D
Polyphen		0.75	.;.;P
Vest4		0.86
MutPred		0.67		Loss of MoRF binding (P = 0.1185);Loss of MoRF binding (P = 0.1185);Loss of MoRF binding (P = 0.1185);
MVP		0.82
MPC		0.86
ClinPred		0.80	D
GERP RS		3.4
Varity_R		0.34
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chr1-16350415;