rs371202740

Variant names:

• chr1-16033649-T-C
• rs371202740
• NM_004070.4:c.2055T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-16033649-T-C
• chr1-16033649-T-A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004070.4(CLCNKA):​c.2055T>C​(p.Ala685Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00895 in 121,428 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (7 hom., cov: 21)
  • Exomes 𝑓: 0.0040 (38 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLCNKA NM_004070.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.574
• 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: AR, Unknown Classification: MODERATE, LIMITED Submitted by: G2P, Ambry Genetics
• Bartter syndrome type 4

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-16033649-T-C is Benign according to our data. Variant chr1-16033649-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 447087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.574 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 7 AR,Unknown gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKA	NM_004070.4	MANE Select	c.2055T>C	p.Ala685Ala	synonymous	Exon 20 of 20	NP_004061.3
	CLCNKA	NM_001042704.2		c.2052T>C	p.Ala684Ala	synonymous	Exon 20 of 20	NP_001036169.1	P51800-3
	CLCNKA	NM_001257139.2		c.1926T>C	p.Ala642Ala	synonymous	Exon 19 of 19	NP_001244068.1	P51800-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKA	ENST00000331433.5	TSL:1 MANE Select	c.2055T>C	p.Ala685Ala	synonymous	Exon 20 of 20	ENSP00000332771.4	P51800-1
	CLCNKA	ENST00000375692.5	TSL:1	c.2052T>C	p.Ala684Ala	synonymous	Exon 21 of 21	ENSP00000364844.1	P51800-3
	CLCNKA	ENST00000861487.1		c.2094T>C	p.Ala698Ala	synonymous	Exon 20 of 20	ENSP00000531546.1

Frequencies

GnomAD3 genomes AF: 0.00893 AC: 1084 AN: 121380 Hom.: 7 Cov.: 21

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00515

Gnomad ASJ AF: 0.00787

Gnomad EAS AF: 0.000547

Gnomad SAS AF: 0.00656

Gnomad FIN AF: 0.0317

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00729

Gnomad OTH AF: 0.00731

GnomAD2 exomes AF: 0.00681 AC: 1541 AN: 226374 AF XY: 0.00681

Gnomad AFR exome AF: 0.00652

Gnomad AMR exome AF: 0.00384

Gnomad ASJ exome AF: 0.00478

Gnomad EAS exome AF: 0.00118

Gnomad FIN exome AF: 0.0147

Gnomad NFE exome AF: 0.00799

Gnomad OTH exome AF: 0.00654

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00401 AC: 5234 AN: 1303772 Hom.: 38 Cov.: 41 AF XY: 0.00414 AC XY: 2680 AN XY: 647268

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00565 AC: 167 AN: 29582

American (AMR) AF: 0.00217 AC: 86 AN: 39598

Ashkenazi Jewish (ASJ) AF: 0.00558 AC: 111 AN: 19888

East Asian (EAS) AF: 0.00215 AC: 51 AN: 23704

South Asian (SAS) AF: 0.00384 AC: 324 AN: 84306

European-Finnish (FIN) AF: 0.0226 AC: 952 AN: 42158

Middle Eastern (MID) AF: 0.00492 AC: 24 AN: 4876

European-Non Finnish (NFE) AF: 0.00324 AC: 3267 AN: 1009276

Other (OTH) AF: 0.00500 AC: 252 AN: 50384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00895 AC: 1087 AN: 121428 Hom.: 7 Cov.: 21 AF XY: 0.00997 AC XY: 564 AN XY: 56586

African (AFR) AF: 0.0109 AC: 344 AN: 31494

American (AMR) AF: 0.00514 AC: 49 AN: 9532

Ashkenazi Jewish (ASJ) AF: 0.00787 AC: 25 AN: 3176

East Asian (EAS) AF: 0.000547 AC: 2 AN: 3656

South Asian (SAS) AF: 0.00658 AC: 23 AN: 3496

European-Finnish (FIN) AF: 0.0317 AC: 182 AN: 5734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 176

European-Non Finnish (NFE) AF: 0.00730 AC: 450 AN: 61684

Other (OTH) AF: 0.00727 AC: 12 AN: 1650

Alfa AF: 0.00849 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.1
DANN	Benign	0.55
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism

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: rs371202740; hg19: chr1-16360144; COSMIC: COSV58890756; COSMIC: COSV58890756;