Variant chr1-16022705-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004070.4(CLCNKA):c.86G>A(p.Arg29His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,538,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CLCNKA
NM_004070.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.21

Variant links:

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]

CLCNKA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.2937315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CLCNKA	NM_004070.4 linkuse as main transcript	c.86G>A	p.Arg29His	missense_variant	2/20	ENST00000331433.5	NP_004061.3
CLCNKA	NM_001042704.2 linkuse as main transcript	c.86G>A	p.Arg29His	missense_variant	2/20		NP_001036169.1
CLCNKA	NM_001257139.2 linkuse as main transcript	c.86G>A	p.Arg29His	missense_variant	2/19		NP_001244068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCNKA	ENST00000331433.5 linkuse as main transcript	c.86G>A	p.Arg29His	missense_variant	2/20	1	NM_004070.4	ENSP00000332771	P4	P51800-1

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000786

AC:

AN:

152698

Hom.:

AF XY:

0.0000622

AC XY:

AN XY:

80390

show subpopulations

Gnomad AFR exome

AF:

0.0000984

Gnomad AMR exome

AF:

0.000129

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000113

Gnomad OTH exome

AF:

0.000243

GnomAD4 exome

AF:

0.000109

AC:

151

AN:

1386846

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

683664

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000662

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000129

Gnomad4 OTH exome

AF:

0.0000696

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000536

Hom.:

Bravo

AF:

0.0000491

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000514

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2023

The c.86G>A (p.R29H) alteration is located in exon 2 (coding exon 1) of the CLCNKA gene. This alteration results from a G to A substitution at nucleotide position 86, causing the arginine (R) at amino acid position 29 to be replaced by a histidine (H). 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

Benign

0.12

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

.;.;T

Eigen

Benign

0.053

Eigen_PC

Benign

-0.075

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.057

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Uncertain

2.3

M;M;M

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.9

N;N;N

REVEL

Uncertain

0.37

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.010

D;D;D

Polyphen

0.99

.;.;D

Vest4

0.36

MVP

0.82

MPC

0.50

ClinPred

0.16

GERP RS

2.0

Varity_R

0.17

gMVP

0.25

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over