Genetic Variant NM_001286.5:c.13A>C (chr1-11806275-A-C) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_001286.5(CLCN6):c.13A>C(p.Arg5Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,337,810 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: 0.0000015 ( 0 hom. )

Consequence

CLCN6
NM_001286.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

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: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP7

Synonymous conserved (PhyloP=1.63 with no splicing effect.

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>C	p.Arg5Arg	synonymous	Exon 1 of 23	NP_001277.2	P51797-1
CLCN6	NM_001256959.2		c.13A>C	p.Arg5Arg	synonymous	Exon 1 of 22	NP_001243888.2	P51797-6
CLCN6	NR_046428.2		n.85A>C		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>C	p.Arg5Arg	synonymous	Exon 1 of 23	ENSP00000234488.9	P51797-1
CLCN6	ENST00000376490.7	TSL:1	n.13A>C		non_coding_transcript_exon	Exon 1 of 11
CLCN6	ENST00000376491.7	TSL:1	n.13A>C		non_coding_transcript_exon	Exon 1 of 11

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000149

AC:

AN:

1337810

Hom.:

Cov.:

AF XY:

0.00000303

AC XY:

AN XY:

660334

show subpopulations

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:

0.00000189

AC:

AN:

1059950

Other (OTH)

AF:

0.00

AC:

AN:

55012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

1.6

PromoterAI

0.0076

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over