1-16030006-G-A

Position:

chr1-16030006-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004070.4(CLCNKA):c.1339G>A(p.Ala447Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 1,588,384 control chromosomes in the GnomAD database, including 254,002 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.59 ( 27511 hom., cov: 32)

Exomes 𝑓: 0.55 ( 226491 hom. )

Consequence

CLCNKA
NM_004070.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.320

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:

CLCNKA (HGNC:):

CLCNKA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.136834E-6).

BP6

Variant 1-16030006-G-A is Benign according to our data. Variant chr1-16030006-G-A is described in ClinVar as [Benign]. Clinvar id is 1177821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCNKA	NM_004070.4 linkuse as main transcript	c.1339G>A	p.Ala447Thr	missense_variant	14/20	ENST00000331433.5	NP_004061.3	P51800-1
CLCNKA	NM_001042704.2 linkuse as main transcript	c.1339G>A	p.Ala447Thr	missense_variant	14/20		NP_001036169.1	P51800-3
CLCNKA	NM_001257139.2 linkuse as main transcript	c.1210G>A	p.Ala404Thr	missense_variant	13/19		NP_001244068.1	P51800-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCNKA	ENST00000331433.5 linkuse as main transcript	c.1339G>A	p.Ala447Thr	missense_variant	14/20	1	NM_004070.4	ENSP00000332771.4		P51800-1

Frequencies

GnomAD3 genomes

AF:

0.593

AC:

89998

AN:

151850

Hom.:

27483

Cov.:

show subpopulations

Gnomad AFR

AF:

0.720

Gnomad AMI

AF:

0.378

Gnomad AMR

AF:

0.469

Gnomad ASJ

AF:

0.446

Gnomad EAS

AF:

0.778

Gnomad SAS

AF:

0.568

Gnomad FIN

AF:

0.506

Gnomad MID

AF:

0.633

Gnomad NFE

AF:

0.554

Gnomad OTH

AF:

0.594

GnomAD3 exomes

AF:

0.548

AC:

136942

AN:

250078

Hom.:

38829

AF XY:

0.549

AC XY:

74350

AN XY:

135360

show subpopulations

Gnomad AFR exome

AF:

0.721

Gnomad AMR exome

AF:

0.378

Gnomad ASJ exome

AF:

0.450

Gnomad EAS exome

AF:

0.756

Gnomad SAS exome

AF:

0.548

Gnomad FIN exome

AF:

0.519

Gnomad NFE exome

AF:

0.555

Gnomad OTH exome

AF:

0.539

GnomAD4 exome

AF:

0.553

AC:

795047

AN:

1436416

Hom.:

226491

Cov.:

AF XY:

0.553

AC XY:

395978

AN XY:

715580

show subpopulations

Gnomad4 AFR exome

AF:

0.735

Gnomad4 AMR exome

AF:

0.388

Gnomad4 ASJ exome

AF:

0.452

Gnomad4 EAS exome

AF:

0.735

Gnomad4 SAS exome

AF:

0.545

Gnomad4 FIN exome

AF:

0.520

Gnomad4 NFE exome

AF:

0.552

Gnomad4 OTH exome

AF:

0.569

GnomAD4 genome

AF:

0.593

AC:

90063

AN:

151968

Hom.:

27511

Cov.:

AF XY:

0.585

AC XY:

43451

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.720

Gnomad4 AMR

AF:

0.468

Gnomad4 ASJ

AF:

0.446

Gnomad4 EAS

AF:

0.777

Gnomad4 SAS

AF:

0.568

Gnomad4 FIN

AF:

0.506

Gnomad4 NFE

AF:

0.554

Gnomad4 OTH

AF:

0.592

Alfa

AF:

0.555

Hom.:

28246

Bravo

AF:

0.592

TwinsUK

AF:

0.548

AC:

2033

ALSPAC

AF:

0.544

AC:

2098

ESP6500AA

AF:

0.713

AC:

3140

ESP6500EA

AF:

0.544

AC:

4681

ExAC

AF:

0.560

AC:

68019

Asia WGS

AF:

0.630

AC:

2188

AN:

3478

EpiCase

AF:

0.546

EpiControl

AF:

0.552

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 17510212) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 16, 2021

Variant summary: CLCNKA c.1339G>A (p.Ala447Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.55 in 250078 control chromosomes, suggesting that it is the major allele and therefore benign. The observed variant frequency is approximately 490 fold of the estimated maximal expected allele frequency for a pathogenic variant in CLCNKA causing Bartter Syndrome, Type 4b phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1339G>A in individuals affected with Bartter Syndrome, Type 4b and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Bartter disease type 4B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Benign

1.1

DANN

Benign

0.85

DEOGEN2

Benign

0.30

.;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.47

T;T;T

MetaRNN

Benign

0.0000031

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.6

L;.;L

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.10

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.30

T;T;T

Polyphen

0.0020

.;.;B

Vest4

0.029

MPC

0.23

ClinPred

0.0056

GERP RS

0.33

Varity_R

0.048

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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