Genetic Variant CLCN6:c.-137C>T (chr1-11806126-C-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4BP6_Very_StrongBA1

The ENST00000312413(CLCN6):c.-137C>T variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.0455 in 640,040 control chromosomes in the GnomAD database, including 792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 153 hom., cov: 33)

Exomes 𝑓: 0.048 ( 639 hom. )

Consequence

CLCN6
ENST00000312413 5_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.66

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.14).

BP6

Variant 1-11806126-C-T is Benign according to our data. Variant chr1-11806126-C-T is described in ClinVar as [Benign]. Clinvar id is 1170440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN6	NM_001286.5 link	c.-137C>T		upstream_gene_variant		ENST00000346436.11	NP_001277.2	P51797-1
MTHFR	NM_005957.5 link	c.-252G>A		upstream_gene_variant		ENST00000376590.9	NP_005948.3	P42898-1Q8IU67Q59GJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN6	ENST00000346436.11 link	c.-137C>T		upstream_gene_variant		1	NM_001286.5	ENSP00000234488.9		P51797-1
MTHFR	ENST00000376590.9 link	c.-252G>A		upstream_gene_variant		1	NM_005957.5	ENSP00000365775.3		P42898-1

Frequencies

GnomAD3 genomes

AF:

0.0371

AC:

5643

AN:

152200

Hom.:

151

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0110

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.0404

Gnomad ASJ

AF:

0.0542

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0423

Gnomad FIN

AF:

0.0316

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0542

Gnomad OTH

AF:

0.0416

GnomAD4 exome

AF:

0.0481

AC:

23475

AN:

487722

Hom.:

639

Cov.:

AF XY:

0.0483

AC XY:

11711

AN XY:

242544

show subpopulations

Gnomad4 AFR exome

AF:

0.0115

AC:

128

AN:

11146

Gnomad4 AMR exome

AF:

0.0339

AC:

262

AN:

7736

Gnomad4 ASJ exome

AF:

0.0506

AC:

541

AN:

10702

Gnomad4 EAS exome

AF:

0.00583

AC:

139

AN:

23838

Gnomad4 SAS exome

AF:

0.0380

AC:

538

AN:

14166

Gnomad4 FIN exome

AF:

0.0328

AC:

1125

AN:

34314

Gnomad4 NFE exome

AF:

0.0538

AC:

19289

AN:

358646

Gnomad4 Remaining exome

AF:

0.0456

AC:

1097

AN:

24080

Heterozygous variant carriers

1161

2321

3482

4642

5803

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

594

1188

1782

2376

2970

<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:

0.0371

AC:

5648

AN:

152318

Hom.:

153

Cov.:

AF XY:

0.0371

AC XY:

2762

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0109

AC:

0.0109187

AN:

0.0109187

Gnomad4 AMR

AF:

0.0404

AC:

0.0403869

AN:

0.0403869

Gnomad4 ASJ

AF:

0.0542

AC:

0.0541787

AN:

0.0541787

Gnomad4 EAS

AF:

0.00174

AC:

0.00173678

AN:

0.00173678

Gnomad4 SAS

AF:

0.0421

AC:

0.0420813

AN:

0.0420813

Gnomad4 FIN

AF:

0.0316

AC:

0.0316325

AN:

0.0316325

Gnomad4 NFE

AF:

0.0542

AC:

0.0542356

AN:

0.0542356

Gnomad4 OTH

AF:

0.0449

AC:

0.0449385

AN:

0.0449385

Heterozygous variant carriers

272

544

817

1089

1361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0487

Hom.:

255

Bravo

AF:

0.0363

Asia WGS

AF:

0.0310

AC:

109

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Benign:1

May 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.14

CADD

Benign

DANN

Benign

0.95

Mutation Taster

=99/1

polymorphism

Splicing

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