Genetic Variant NM_004070.4:c.92C>A (chr1-16022711-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004070.4(CLCNKA):c.92C>A(p.Ala31Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A31G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

CLCNKA
NM_004070.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.619

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

Bartter disease type 4B
Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, G2P
Bartter syndrome type 4
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CLCNKA links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05417639).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKA	NM_004070.4 link	c.92C>A	p.Ala31Asp	missense_variant	Exon 2 of 20	ENST00000331433.5	NP_004061.3	P51800-1
CLCNKA	NM_001042704.2 link	c.92C>A	p.Ala31Asp	missense_variant	Exon 2 of 20		NP_001036169.1	P51800-3
CLCNKA	NM_001257139.2 link	c.92C>A	p.Ala31Asp	missense_variant	Exon 2 of 19		NP_001244068.1	P51800-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKA	ENST00000331433.5 link	c.92C>A	p.Ala31Asp	missense_variant	Exon 2 of 20	1	NM_004070.4	ENSP00000332771.4		P51800-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.23e-7

AC:

AN:

1383668

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

681618

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31824

American (AMR)

AF:

0.00

AC:

AN:

34490

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23458

East Asian (EAS)

AF:

0.00

AC:

AN:

36428

South Asian (SAS)

AF:

0.00

AC:

AN:

74820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48662

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5566

European-Non Finnish (NFE)

AF:

9.34e-7

AC:

AN:

1071068

Other (OTH)

AF:

0.00

AC:

AN:

57352

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

4.0

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.083

.;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.37

T;T;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.054

T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.0

N;N;N

PhyloP100

-0.62

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.77

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.55

T;T;T

Sift4G

Benign

0.63

T;T;T

Polyphen

0.0050

.;.;B

Vest4

0.064

MutPred

0.43

Loss of MoRF binding (P = 0.0436);Loss of MoRF binding (P = 0.0436);Loss of MoRF binding (P = 0.0436);

MVP

0.38

MPC

0.53

ClinPred

0.52

GERP RS

2.2

Varity_R

0.059

gMVP

0.20

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over