dbSNP rs1023252: CLCN6:c.2529+316G>A (chr1-11838976-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001286.5(CLCN6):c.2529+316G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 542,982 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

CLCN6
NM_001286.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.846

Publications

64 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09444821).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CLCN6	NM_001286.5 link	c.2529+316G>A	intron_variant	Intron 22 of 22	ENST00000346436.11	NP_001277.2	P51797-1
CLCN6	NM_001256959.2 link	c.2463+316G>A	intron_variant	Intron 21 of 21		NP_001243888.2	P51797-6
CLCN6	NR_046428.2 link	n.2585+316G>A	intron_variant	Intron 22 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLCN6	ENST00000346436.11 link	c.2529+316G>A		intron_variant	Intron 22 of 22	1	NM_001286.5	ENSP00000234488.9	P51797-1
CLCN6	ENST00000376496.4 link	c.2845G>A	p.Asp949Asn	missense_variant	Exon 22 of 22	5		ENSP00000365679.3	P51797-5
CLCN6	ENST00000312413.10 link	c.2463+316G>A		intron_variant	Intron 21 of 21	2		ENSP00000308367.7	P51797-6
CLCN6	ENST00000400892.3 link	n.*1022+316G>A		intron_variant	Intron 22 of 26	3		ENSP00000496938.1	A0A3B3IRY0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000685

AC:

AN:

146004

AF XY:

0.0000128

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000184

AC:

AN:

542982

Hom.:

Cov.:

AF XY:

0.00000346

AC XY:

AN XY:

288996

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15344

American (AMR)

AF:

0.00

AC:

AN:

33634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19542

East Asian (EAS)

AF:

0.00

AC:

AN:

31486

South Asian (SAS)

AF:

0.0000161

AC:

AN:

62024

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47436

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4000

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

299846

Other (OTH)

AF:

0.00

AC:

AN:

29670

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.68

(source)

DANN

Benign

0.94

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0090

LIST_S2

Benign

0.36

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.094

MetaSVM

Benign

-0.43

PhyloP100

-0.85

PROVEAN

Benign

0.12

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Vest4

0.034

MutPred

0.13

Gain of MoRF binding (P = 0.0513);

MVP

0.47

ClinPred

0.15

GERP RS

-6.3

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over