Genetic Variant NM_004070.4:c.101-33A>G (chr1-16023767-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004070.4(CLCNKA):c.101-33A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0915 in 1,612,362 control chromosomes in the GnomAD database, including 7,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.089 ( 692 hom., cov: 33)

Exomes 𝑓: 0.092 ( 6756 hom. )

Consequence

CLCNKA
NM_004070.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.589

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 1-16023767-A-G is Benign according to our data. Variant chr1-16023767-A-G is described in ClinVar as [Benign]. Clinvar id is 1222414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CLCNKA	NM_004070.4 link	c.101-33A>G	intron_variant	Intron 2 of 19	ENST00000331433.5	NP_004061.3	P51800-1
CLCNKA	NM_001042704.2 link	c.101-33A>G	intron_variant	Intron 2 of 19		NP_001036169.1	P51800-3
CLCNKA	NM_001257139.2 link	c.101-33A>G	intron_variant	Intron 2 of 18		NP_001244068.1	P51800-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKA	ENST00000331433.5 link	c.101-33A>G		intron_variant	Intron 2 of 19	1	NM_004070.4	ENSP00000332771.4		P51800-1

Frequencies

GnomAD3 genomes

AF:

0.0886

AC:

13471

AN:

152118

Hom.:

688

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0898

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0629

Gnomad ASJ

AF:

0.0426

Gnomad EAS

AF:

0.00424

Gnomad SAS

AF:

0.0422

Gnomad FIN

AF:

0.119

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.0783

GnomAD3 exomes

AF:

0.0760

AC:

19040

AN:

250544

Hom.:

914

AF XY:

0.0754

AC XY:

10225

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.0897

Gnomad AMR exome

AF:

0.0383

Gnomad ASJ exome

AF:

0.0355

Gnomad EAS exome

AF:

0.00239

Gnomad SAS exome

AF:

0.0442

Gnomad FIN exome

AF:

0.129

Gnomad NFE exome

AF:

0.0994

Gnomad OTH exome

AF:

0.0798

GnomAD4 exome

AF:

0.0918

AC:

134007

AN:

1460126

Hom.:

6756

Cov.:

AF XY:

0.0901

AC XY:

65430

AN XY:

726418

show subpopulations

Gnomad4 AFR exome

AF:

0.0915

Gnomad4 AMR exome

AF:

0.0405

Gnomad4 ASJ exome

AF:

0.0402

Gnomad4 EAS exome

AF:

0.00696

Gnomad4 SAS exome

AF:

0.0434

Gnomad4 FIN exome

AF:

0.125

Gnomad4 NFE exome

AF:

0.101

Gnomad4 OTH exome

AF:

0.0859

GnomAD4 genome

AF:

0.0886

AC:

13490

AN:

152236

Hom.:

692

Cov.:

AF XY:

0.0859

AC XY:

6398

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0900

Gnomad4 AMR

AF:

0.0628

Gnomad4 ASJ

AF:

0.0426

Gnomad4 EAS

AF:

0.00425

Gnomad4 SAS

AF:

0.0423

Gnomad4 FIN

AF:

0.119

Gnomad4 NFE

AF:

0.102

Gnomad4 OTH

AF:

0.0770

Alfa

AF:

0.0942

Hom.:

164

Bravo

AF:

0.0830

Asia WGS

AF:

0.0350

AC:

123

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

0.52

DANN

Benign

0.45

BranchPoint Hunter

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over