1-16022841-C-T

Variant names:

• chr1-16022841-C-T
• rs61771056
• NM_004070.4:c.100+122C>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.100+122C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 665,266 control chromosomes in the GnomAD database, including 5,611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1160 hom., cov: 33)
  • Exomes 𝑓: 0.12 (4451 hom.)
• Consequence: CLCNKA NM_004070.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0180
• Publications: 2 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 (BayesDel_noAF=-0.9).
• BP6: Variant 1-16022841-C-T is Benign according to our data. Variant chr1-16022841-C-T is described in ClinVar as [Benign]. Clinvar id is 1287202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKA	NM_004070.4	c.100+122C>T		intron_variant	Intron 2 of 19	ENST00000331433.5	NP_004061.3
CLCNKA	NM_001042704.2	c.100+122C>T		intron_variant	Intron 2 of 19		NP_001036169.1
CLCNKA	NM_001257139.2	c.100+122C>T		intron_variant	Intron 2 of 18		NP_001244068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKA	ENST00000331433.5	c.100+122C>T		intron_variant	Intron 2 of 19	1	NM_004070.4	ENSP00000332771.4

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16355 AN: 152152 Hom.: 1155 Cov.: 33

Gnomad AFR AF: 0.0377

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.0686

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.111

GnomAD4 exome AF: 0.122 AC: 62802 AN: 512996 Hom.: 4451 AF XY: 0.121 AC XY: 31472 AN XY: 260740

African (AFR) AF: 0.0339 AC: 483 AN: 14258

American (AMR) AF: 0.193 AC: 3111 AN: 16108

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 1624 AN: 12780

East Asian (EAS) AF: 0.249 AC: 6997 AN: 28142

South Asian (SAS) AF: 0.0612 AC: 1881 AN: 30750

European-Finnish (FIN) AF: 0.195 AC: 5624 AN: 28898

Middle Eastern (MID) AF: 0.102 AC: 371 AN: 3650

European-Non Finnish (NFE) AF: 0.113 AC: 39563 AN: 350854

Other (OTH) AF: 0.114 AC: 3148 AN: 27556

GnomAD4 genome AF: 0.107 AC: 16365 AN: 152270 Hom.: 1160 Cov.: 33 AF XY: 0.114 AC XY: 8459 AN XY: 74454

African (AFR) AF: 0.0377 AC: 1566 AN: 41576

American (AMR) AF: 0.171 AC: 2614 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 484 AN: 3468

East Asian (EAS) AF: 0.194 AC: 1002 AN: 5166

South Asian (SAS) AF: 0.0682 AC: 329 AN: 4822

European-Finnish (FIN) AF: 0.199 AC: 2116 AN: 10616

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7825 AN: 68004

Other (OTH) AF: 0.112 AC: 237 AN: 2112

Alfa AF: 0.106 Hom.: 128

Bravo AF: 0.105

Asia WGS AF: 0.160 AC: 556 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.1
DANN	Benign	0.29
PhyloP100		-0.018
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61771056; hg19: chr1-16349336; COSMIC: COSV107334881; COSMIC: COSV107334881;