rs3737965

Variant names:

• chr1-11806394-G-A
• rs3737965
• NM_001286.5:c.87+45G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001286.5(CLCN6):​c.87+45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0509 in 1,454,100 control chromosomes in the GnomAD database, including 2,228 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 0.043 (210 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2018 hom.)
• Consequence: CLCN6 NM_001286.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.49
• Publications: 28 publications found

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]

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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN6	NM_001286.5	c.87+45G>A		intron_variant	Intron 1 of 22	ENST00000346436.11	NP_001277.2
CLCN6	NM_001256959.2	c.87+45G>A		intron_variant	Intron 1 of 21		NP_001243888.2
CLCN6	NR_046428.2	n.159+45G>A		intron_variant	Intron 1 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN6	ENST00000346436.11	c.87+45G>A		intron_variant	Intron 1 of 22	1	NM_001286.5	ENSP00000234488.9

Frequencies

GnomAD3 genomes AF: 0.0435 AC: 6615 AN: 152028 Hom.: 211 Cov.: 32

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0435

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0159

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0467

Gnomad OTH AF: 0.0445

GnomAD2 exomes AF: 0.0503 AC: 3575 AN: 71084 AF XY: 0.0540

Gnomad AFR exome AF: 0.0334

Gnomad AMR exome AF: 0.0410

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.0143

Gnomad NFE exome AF: 0.0477

Gnomad OTH exome AF: 0.0387

GnomAD4 exome AF: 0.0517 AC: 67366 AN: 1301956 Hom.: 2018 Cov.: 26 AF XY: 0.0525 AC XY: 33690 AN XY: 642026

African (AFR) AF: 0.0251 AC: 627 AN: 24978

American (AMR) AF: 0.0410 AC: 580 AN: 14148

Ashkenazi Jewish (ASJ) AF: 0.0169 AC: 374 AN: 22096

East Asian (EAS) AF: 0.104 AC: 2982 AN: 28698

South Asian (SAS) AF: 0.0927 AC: 6026 AN: 65024

European-Finnish (FIN) AF: 0.0180 AC: 771 AN: 42948

Middle Eastern (MID) AF: 0.0189 AC: 77 AN: 4084

European-Non Finnish (NFE) AF: 0.0505 AC: 52795 AN: 1046086

Other (OTH) AF: 0.0582 AC: 3134 AN: 53894

GnomAD4 genome AF: 0.0435 AC: 6612 AN: 152144 Hom.: 210 Cov.: 32 AF XY: 0.0431 AC XY: 3206 AN XY: 74400

African (AFR) AF: 0.0307 AC: 1273 AN: 41518

American (AMR) AF: 0.0432 AC: 661 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3470

East Asian (EAS) AF: 0.122 AC: 628 AN: 5148

South Asian (SAS) AF: 0.113 AC: 542 AN: 4810

European-Finnish (FIN) AF: 0.0159 AC: 169 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0467 AC: 3173 AN: 67960

Other (OTH) AF: 0.0450 AC: 95 AN: 2112

Alfa AF: 0.0432 Hom.: 76

Bravo AF: 0.0433

Asia WGS AF: 0.111 AC: 383 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Benign	0.94
PhyloP100		3.5
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3737965; hg19: chr1-11866451; COSMIC: COSV56743387; COSMIC: COSV56743387;