Genetic Variant NM_001286.5:c.346+88A>G (chr1-11819642-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001286.5(CLCN6):c.346+88A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,136,242 control chromosomes in the GnomAD database, including 15,465 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.18 ( 2660 hom., cov: 33)

Exomes 𝑓: 0.16 ( 12805 hom. )

Consequence

CLCN6
NM_001286.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.530

Publications

23 publications found

Variant links:

Genes affected

CLCN6 (HGNC:2024): (chloride voltage-gated channel 6) This gene encodes a member of the voltage-dependent chloride channel protein family. Members of this family can function as either chloride channels or antiporters. This protein is primarily localized to late endosomes and functions as a chloride/proton antiporter. Alternate splicing results in both coding and non-coding variants. Additional alternately spliced variants have been described but their full-length structure is unknown. [provided by RefSeq, Mar 2012]

CLCN6 Gene-Disease associations (from GenCC):

neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

CLCN6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CLCN6	NM_001286.5 link	c.346+88A>G	intron_variant	Intron 5 of 22	ENST00000346436.11	NP_001277.2	P51797-1
CLCN6	NM_001256959.2 link	c.280+88A>G	intron_variant	Intron 4 of 21		NP_001243888.2	P51797-6
CLCN6	NR_046428.2 link	n.418+88A>G	intron_variant	Intron 5 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN6	ENST00000346436.11 link	c.346+88A>G		intron_variant	Intron 5 of 22	1	NM_001286.5	ENSP00000234488.9		P51797-1

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27232

AN:

152054

Hom.:

2652

Cov.:

show subpopulations

Gnomad AFR

AF:

0.256

Gnomad AMI

AF:

0.0844

Gnomad AMR

AF:

0.122

Gnomad ASJ

AF:

0.0969

Gnomad EAS

AF:

0.127

Gnomad SAS

AF:

0.200

Gnomad FIN

AF:

0.157

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.157

Gnomad OTH

AF:

0.154

GnomAD4 exome

AF:

0.159

AC:

156800

AN:

984070

Hom.:

12805

AF XY:

0.160

AC XY:

81021

AN XY:

507008

show subpopulations

African (AFR)

AF:

0.261

AC:

6214

AN:

23816

American (AMR)

AF:

0.102

AC:

4183

AN:

41164

Ashkenazi Jewish (ASJ)

AF:

0.0957

AC:

2187

AN:

22856

East Asian (EAS)

AF:

0.113

AC:

4209

AN:

37232

South Asian (SAS)

AF:

0.183

AC:

13870

AN:

75600

European-Finnish (FIN)

AF:

0.145

AC:

7627

AN:

52734

Middle Eastern (MID)

AF:

0.169

AC:

807

AN:

4784

European-Non Finnish (NFE)

AF:

0.162

AC:

110329

AN:

681350

Other (OTH)

AF:

0.166

AC:

7374

AN:

44534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

6495

12990

19486

25981

32476

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3172

6344

9516

12688

15860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.179

AC:

27273

AN:

152172

Hom.:

2660

Cov.:

AF XY:

0.179

AC XY:

13331

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.257

AC:

10647

AN:

41504

American (AMR)

AF:

0.121

AC:

1856

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0969

AC:

336

AN:

3468

East Asian (EAS)

AF:

0.127

AC:

660

AN:

5190

South Asian (SAS)

AF:

0.200

AC:

965

AN:

4824

European-Finnish (FIN)

AF:

0.157

AC:

1666

AN:

10578

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.157

AC:

10691

AN:

68006

Other (OTH)

AF:

0.158

AC:

333

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1140

2280

3420

4560

5700

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

304

608

912

1216

1520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.160

Hom.:

2779

Bravo

AF:

0.178

Asia WGS

AF:

0.171

AC:

595

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

6.0

(source)

DANN

Benign

0.26

PhyloP100

0.53

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over