dbSNP rs765083898: CLCNKA:p.Asp14Asn (chr1-16022659-G-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.40G>A(p.Asp14Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000706 in 1,415,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. D14Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000071 ( 0 hom. )

Consequence

CLCNKA
NM_004070.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.167

Publications

0 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:

Genome browser will be placed here

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=0.02870667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKA	NM_004070.4 link	c.40G>A	p.Asp14Asn	missense_variant	Exon 2 of 20	ENST00000331433.5	NP_004061.3	P51800-1
CLCNKA	NM_001042704.2 link	c.40G>A	p.Asp14Asn	missense_variant	Exon 2 of 20		NP_001036169.1	P51800-3
CLCNKA	NM_001257139.2 link	c.40G>A	p.Asp14Asn	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.40G>A	p.Asp14Asn	missense_variant	Exon 2 of 20	1	NM_004070.4	ENSP00000332771.4		P51800-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000111

AC:

AN:

179492

AF XY:

0.0000105

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000706

AC:

AN:

1415780

Hom.:

Cov.:

AF XY:

0.0000100

AC XY:

AN XY:

700156

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32776

American (AMR)

AF:

0.00

AC:

AN:

37960

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24864

East Asian (EAS)

AF:

0.00

AC:

AN:

37756

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79616

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.00000827

AC:

AN:

1088186

Other (OTH)

AF:

0.00

AC:

AN:

58688

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000841

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

4.9

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.055

.;.;T

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.0039

LIST_S2

Benign

0.63

T;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.029

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

-1.4

N;N;N

PhyloP100

0.17

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.13

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.75

T;T;T

Sift4G

Benign

0.44

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.063

MutPred

0.22

Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);

MVP

0.62

MPC

0.34

ClinPred

0.018

GERP RS

3.0

Varity_R

0.035

gMVP

0.064

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs765083898

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over