1-16022642-G-A

Position:

• chr1-16022642-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004070.4(CLCNKA):​c.23G>A​(p.Arg8His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,566,692 control chromosomes in the GnomAD database, including 397 homozygotes. In-silico tool predicts 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 0.014 (28 hom., cov: 33)
  • Exomes 𝑓: 0.020 (369 hom.)
• Consequence: CLCNKA NM_004070.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.718

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041867197).
• BP6: Variant 1-16022642-G-A is Benign according to our data. Variant chr1-16022642-G-A is described in ClinVar as [Benign]. Clinvar id is 1220926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16022642-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0145 (2205/152276) while in subpopulation SAS AF= 0.0351 (169/4820). AF 95% confidence interval is 0.0307. There are 28 homozygotes in gnomad4. There are 1051 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCNKA	NM_004070.4	c.23G>A	p.Arg8His	missense_variant	2/20	ENST00000331433.5	NP_004061.3
CLCNKA	NM_001042704.2	c.23G>A	p.Arg8His	missense_variant	2/20		NP_001036169.1
CLCNKA	NM_001257139.2	c.23G>A	p.Arg8His	missense_variant	2/19		NP_001244068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCNKA	ENST00000331433.5	c.23G>A	p.Arg8His	missense_variant	2/20	1	NM_004070.4	ENSP00000332771	P4

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2203 AN: 152158 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.00340

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00863

Gnomad ASJ AF: 0.0392

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0348

Gnomad FIN AF: 0.00876

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0216

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0158 AC: 2849 AN: 180034 Hom.: 32 AF XY: 0.0171 AC XY: 1639 AN XY: 95706

Gnomad AFR exome AF: 0.00202

Gnomad AMR exome AF: 0.00664

Gnomad ASJ exome AF: 0.0366

Gnomad EAS exome AF: 0.0000725

Gnomad SAS exome AF: 0.0270

Gnomad FIN exome AF: 0.00748

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0170

GnomAD4 exome AF: 0.0203 AC: 28661 AN: 1414416 Hom.: 369 Cov.: 30 AF XY: 0.0208 AC XY: 14566 AN XY: 699262

Gnomad4 AFR exome AF: 0.00317

Gnomad4 AMR exome AF: 0.00729

Gnomad4 ASJ exome AF: 0.0402

Gnomad4 EAS exome AF: 0.0000530

Gnomad4 SAS exome AF: 0.0294

Gnomad4 FIN exome AF: 0.0101

Gnomad4 NFE exome AF: 0.0213

Gnomad4 OTH exome AF: 0.0186

GnomAD4 genome AF: 0.0145 AC: 2205 AN: 152276 Hom.: 28 Cov.: 33 AF XY: 0.0141 AC XY: 1051 AN XY: 74452

Gnomad4 AFR AF: 0.00339

Gnomad4 AMR AF: 0.00862

Gnomad4 ASJ AF: 0.0392

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0351

Gnomad4 FIN AF: 0.00876

Gnomad4 NFE AF: 0.0216

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0210 Hom.: 77

Bravo AF: 0.0139

TwinsUK AF: 0.0205 AC: 76

ALSPAC AF: 0.0210 AC: 81

ESP6500AA AF: 0.00273 AC: 12

ESP6500EA AF: 0.0212 AC: 182

ExAC AF: 0.0135 AC: 1608

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	.;.;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.84	T;T;T
MetaRNN	Benign	0.0042	T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	3.0	M;M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.027	D;D;D
Sift4G	Benign	0.065	T;T;T
Polyphen		0.25	.;.;B
Vest4		0.081
MPC		0.44
ClinPred		0.023	T
GERP RS		2.1
Varity_R		0.080
gMVP		0.29

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: rs9442189; hg19: chr1-16349137; COSMIC: COSV104403462; COSMIC: COSV104403462;