rs1805152

Variant names:

• chr1-16030006-G-A
• rs1805152
• NM_004070.4:c.1339G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-16030006-G-A
• chr1-16030006-G-C
• chr1-16030006-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (27511 hom., cov: 32)
  • Exomes 𝑓: 0.55 (226491 hom.)
• Consequence: CLCNKA NM_004070.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.320
• Publications: 45 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
CLCNKA	NM_004070.4	c.1339G>A	p.Ala447Thr	missense_variant	Exon 14 of 20	ENST00000331433.5	NP_004061.3
CLCNKA	NM_001042704.2	c.1339G>A	p.Ala447Thr	missense_variant	Exon 14 of 20		NP_001036169.1
CLCNKA	NM_001257139.2	c.1210G>A	p.Ala404Thr	missense_variant	Exon 13 of 19		NP_001244068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKA	ENST00000331433.5	c.1339G>A	p.Ala447Thr	missense_variant	Exon 14 of 20	1	NM_004070.4	ENSP00000332771.4

Frequencies

GnomAD3 genomes AF: 0.593 AC: 89998 AN: 151850 Hom.: 27483 Cov.: 32

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

GnomAD2 exomes AF: 0.548 AC: 136942 AN: 250078 AF XY: 0.549

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 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.: 48 AF XY: 0.553 AC XY: 395978 AN XY: 715580

African (AFR) AF: 0.735 AC: 24446 AN: 33246

American (AMR) AF: 0.388 AC: 17341 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 11773 AN: 26038

East Asian (EAS) AF: 0.735 AC: 29182 AN: 39698

South Asian (SAS) AF: 0.545 AC: 46904 AN: 86028

European-Finnish (FIN) AF: 0.520 AC: 27466 AN: 52832

Middle Eastern (MID) AF: 0.534 AC: 3058 AN: 5730

European-Non Finnish (NFE) AF: 0.552 AC: 600934 AN: 1088542

Other (OTH) AF: 0.569 AC: 33943 AN: 59620

GnomAD4 genome AF: 0.593 AC: 90063 AN: 151968 Hom.: 27511 Cov.: 32 AF XY: 0.585 AC XY: 43451 AN XY: 74264

African (AFR) AF: 0.720 AC: 29855 AN: 41456

American (AMR) AF: 0.468 AC: 7163 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1545 AN: 3464

East Asian (EAS) AF: 0.777 AC: 3996 AN: 5140

South Asian (SAS) AF: 0.568 AC: 2735 AN: 4818

European-Finnish (FIN) AF: 0.506 AC: 5348 AN: 10574

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.554 AC: 37642 AN: 67906

Other (OTH) AF: 0.592 AC: 1250 AN: 2110

Alfa AF: 0.555 Hom.: 41302

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

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17510212) -

not specified Benign:1

Dec 16, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.56	T
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	N
LIST_S2	Benign	0.47	T;T;T
MetaRNN	Benign	0.0000031	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.6	L;.;L
PhyloP100		-0.32
PrimateAI	Benign	0.29	T
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	T
GERP RS		0.33
Varity_R		0.048
gMVP		0.33
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1805152; hg19: chr1-16356501; COSMIC: COSV58890926; COSMIC: COSV58890926;