NM_004070.4:c.1846-6T>C

Variant names:

• chr1-16032437-T-C
• rs10803407
• NM_004070.4:c.1846-6T>C

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.1846-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.677 in 1,608,830 control chromosomes in the GnomAD database, including 372,657 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37830 hom., cov: 33)
  • Exomes 𝑓: 0.67 (334827 hom.)
• Consequence: CLCNKA NM_004070.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005001
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0590
• Publications: 17 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=-0.94).
• BP6: Variant 1-16032437-T-C is Benign according to our data. Variant chr1-16032437-T-C is described in ClinVar as Benign. ClinVar VariationId is 585696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.952 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004070.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKA	NM_004070.4	MANE Select	c.1846-6T>C		splice_region intron	N/A	NP_004061.3
	CLCNKA	NM_001042704.2		c.1846-9T>C		intron	N/A	NP_001036169.1
	CLCNKA	NM_001257139.2		c.1717-6T>C		splice_region intron	N/A	NP_001244068.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKA	ENST00000331433.5	TSL:1 MANE Select	c.1846-6T>C		splice_region intron	N/A	ENSP00000332771.4
	CLCNKA	ENST00000375692.5	TSL:1	c.1846-9T>C		intron	N/A	ENSP00000364844.1
	CLCNKA	ENST00000439316.6	TSL:2	c.1717-6T>C		splice_region intron	N/A	ENSP00000414445.2

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106598 AN: 152028 Hom.: 37803 Cov.: 33

Gnomad AFR AF: 0.761

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.975

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.670

Gnomad OTH AF: 0.705

GnomAD2 exomes AF: 0.682 AC: 171024 AN: 250740 AF XY: 0.678

Gnomad AFR exome AF: 0.764

Gnomad AMR exome AF: 0.597

Gnomad ASJ exome AF: 0.585

Gnomad EAS exome AF: 0.971

Gnomad FIN exome AF: 0.712

Gnomad NFE exome AF: 0.670

Gnomad OTH exome AF: 0.667

GnomAD4 exome AF: 0.675 AC: 983127 AN: 1456684 Hom.: 334827 Cov.: 35 AF XY: 0.673 AC XY: 487813 AN XY: 724878

African (AFR) AF: 0.773 AC: 25829 AN: 33426

American (AMR) AF: 0.603 AC: 26959 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 15267 AN: 26078

East Asian (EAS) AF: 0.982 AC: 38977 AN: 39684

South Asian (SAS) AF: 0.615 AC: 53005 AN: 86174

European-Finnish (FIN) AF: 0.716 AC: 37648 AN: 52550

Middle Eastern (MID) AF: 0.629 AC: 3617 AN: 5754

European-Non Finnish (NFE) AF: 0.668 AC: 740608 AN: 1108076

Other (OTH) AF: 0.684 AC: 41217 AN: 60230

GnomAD4 genome AF: 0.701 AC: 106675 AN: 152146 Hom.: 37830 Cov.: 33 AF XY: 0.699 AC XY: 52020 AN XY: 74384

African (AFR) AF: 0.762 AC: 31612 AN: 41508

American (AMR) AF: 0.634 AC: 9689 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2045 AN: 3472

East Asian (EAS) AF: 0.975 AC: 5050 AN: 5182

South Asian (SAS) AF: 0.636 AC: 3069 AN: 4824

European-Finnish (FIN) AF: 0.706 AC: 7480 AN: 10598

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.670 AC: 45520 AN: 67964

Other (OTH) AF: 0.705 AC: 1484 AN: 2106

Alfa AF: 0.661 Hom.: 12693

Bravo AF: 0.698

Asia WGS AF: 0.791 AC: 2750 AN: 3478

EpiCase AF: 0.655

EpiControl AF: 0.662

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Bartter disease type 4B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.9
DANN	Benign	0.67
PhyloP100		-0.059
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.020
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: rs10803407; hg19: chr1-16358932;