Genetic Variant NM_001286.5:c.13A>G (chr1-11806275-A-G) – 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.13A>G(p.Arg5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CLCN6
NM_001286.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.63

Publications

0 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 links:

MTHFR (HGNC:7436): (methylenetetrahydrofolate reductase) The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]

MTHFR Gene-Disease associations (from GenCC):

homocystinuria due to methylene tetrahydrofolate reductase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

MTHFR 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=0.1348699).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLCN6	NM_001286.5	MANE Select	c.13A>G	p.Arg5Gly	missense	Exon 1 of 23	NP_001277.2	P51797-1
CLCN6	NM_001256959.2		c.13A>G	p.Arg5Gly	missense	Exon 1 of 22	NP_001243888.2	P51797-6
CLCN6	NR_046428.2		n.85A>G		non_coding_transcript_exon	Exon 1 of 23

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLCN6	ENST00000346436.11	TSL:1 MANE Select	c.13A>G	p.Arg5Gly	missense	Exon 1 of 23	ENSP00000234488.9	P51797-1
CLCN6	ENST00000376490.7	TSL:1	n.13A>G		non_coding_transcript_exon	Exon 1 of 11
CLCN6	ENST00000376491.7	TSL:1	n.13A>G		non_coding_transcript_exon	Exon 1 of 11

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1337810

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

660334

African (AFR)

AF:

0.00

AC:

AN:

26212

American (AMR)

AF:

0.00

AC:

AN:

20016

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21746

East Asian (EAS)

AF:

0.00

AC:

AN:

31510

South Asian (SAS)

AF:

0.00

AC:

AN:

67154

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50810

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5400

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1059950

Other (OTH)

AF:

0.00

AC:

AN:

55012

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.16

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.47

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.57

MutationAssessor

Benign

-0.69

PhyloP100

1.6

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.66

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

Sift4G

Benign

0.38

Polyphen

0.0

Vest4

0.16

MutPred

0.23

Gain of relative solvent accessibility (P = 0.0479)

MVP

0.71

MPC

0.43

ClinPred

0.62

GERP RS

1.6

PromoterAI

0.038

Neutral

(source)

Varity_R

0.25

gMVP

0.51

Mutation Taster

=77/23

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over