1-16024780-A-G

Position:

• chr1-16024780-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004070.4(CLCNKA):​c.247A>G​(p.Arg83Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 1,613,634 control chromosomes in the GnomAD database, including 257,855 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (27334 hom., cov: 32)
  • Exomes 𝑓: 0.56 (230521 hom.)
• Consequence: CLCNKA NM_004070.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.107

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8806211E-6).
• BP6: Variant 1-16024780-A-G is Benign according to our data. Variant chr1-16024780-A-G is described in ClinVar as [Benign]. Clinvar id is 585697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCNKA	NM_004070.4	c.247A>G	p.Arg83Gly	missense_variant	4/20	ENST00000331433.5	NP_004061.3
CLCNKA	NM_001042704.2	c.247A>G	p.Arg83Gly	missense_variant	4/20		NP_001036169.1
CLCNKA	NM_001257139.2	c.229+852A>G		intron_variant			NP_001244068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCNKA	ENST00000331433.5	c.247A>G	p.Arg83Gly	missense_variant	4/20	1	NM_004070.4	ENSP00000332771.4

Frequencies

GnomAD3 genomes AF: 0.592 AC: 89861 AN: 151908 Hom.: 27307 Cov.: 32

Gnomad AFR AF: 0.703

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.571

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.637

Gnomad NFE AF: 0.560

Gnomad OTH AF: 0.600

GnomAD3 exomes AF: 0.551 AC: 138274 AN: 251076 Hom.: 39379 AF XY: 0.553 AC XY: 75081 AN XY: 135786

Gnomad AFR exome AF: 0.705

Gnomad AMR exome AF: 0.380

Gnomad ASJ exome AF: 0.464

Gnomad EAS exome AF: 0.757

Gnomad SAS exome AF: 0.553

Gnomad FIN exome AF: 0.522

Gnomad NFE exome AF: 0.560

Gnomad OTH exome AF: 0.545

GnomAD4 exome AF: 0.559 AC: 816601 AN: 1461608 Hom.: 230521 Cov.: 60 AF XY: 0.559 AC XY: 406144 AN XY: 727106

Gnomad4 AFR exome AF: 0.714

Gnomad4 AMR exome AF: 0.391

Gnomad4 ASJ exome AF: 0.467

Gnomad4 EAS exome AF: 0.737

Gnomad4 SAS exome AF: 0.551

Gnomad4 FIN exome AF: 0.522

Gnomad4 NFE exome AF: 0.558

Gnomad4 OTH exome AF: 0.574

GnomAD4 genome AF: 0.592 AC: 89927 AN: 152026 Hom.: 27334 Cov.: 32 AF XY: 0.584 AC XY: 43408 AN XY: 74290

Gnomad4 AFR AF: 0.703

Gnomad4 AMR AF: 0.470

Gnomad4 ASJ AF: 0.455

Gnomad4 EAS AF: 0.780

Gnomad4 SAS AF: 0.571

Gnomad4 FIN AF: 0.510

Gnomad4 NFE AF: 0.560

Gnomad4 OTH AF: 0.599

Alfa AF: 0.569 Hom.: 10775

Bravo AF: 0.591

TwinsUK AF: 0.564 AC: 2092

ALSPAC AF: 0.551 AC: 2124

ESP6500AA AF: 0.696 AC: 3067

ESP6500EA AF: 0.552 AC: 4748

ExAC AF: 0.563 AC: 68366

Asia WGS AF: 0.631 AC: 2195 AN: 3478

EpiCase AF: 0.553

EpiControl AF: 0.559

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 23850580, 21248228) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -

Bartter disease type 4B Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Dec 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	9.0
DANN	Benign	0.89
DEOGEN2	Benign	0.086	.;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.26	T;T
MetaRNN	Benign	0.0000019	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.17	N;N
REVEL	Benign	0.23
Sift	Benign	0.39	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.0	.;B
Vest4		0.095
MPC		0.45
ClinPred		0.0049	T
GERP RS		0.87
Varity_R		0.061
gMVP		0.33

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

Other links and lift over

dbSNP: rs10927887; hg19: chr1-16351275; COSMIC: COSV58890913; COSMIC: COSV58890913;