dbSNP rs13306560: MTHFR:n.-252G>T (chr1-11806126-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000641747.1(MTHFR):n.-252G>T variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.00000205 in 487,976 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: 0.0000020 ( 0 hom. )

Consequence

MTHFR
ENST00000641747.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.66

Publications

0 publications found

Variant links:

Genes affected

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:

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.12).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN6	NM_001286.5 link	c.-137C>A		upstream_gene_variant		ENST00000346436.11	NP_001277.2	P51797-1
MTHFR	NM_005957.5 link	c.-252G>T		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>A		upstream_gene_variant		1	NM_001286.5	ENSP00000234488.9		P51797-1
MTHFR	ENST00000376590.9 link	c.-252G>T		upstream_gene_variant		1	NM_005957.5	ENSP00000365775.3		P42898-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

487976

Hom.:

Cov.:

AF XY:

0.00000412

AC XY:

AN XY:

242684

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

11146

American (AMR)

AF:

0.00

AC:

AN:

7738

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10704

East Asian (EAS)

AF:

0.00

AC:

AN:

23838

South Asian (SAS)

AF:

0.00

AC:

AN:

14174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3096

European-Non Finnish (NFE)

AF:

0.00000279

AC:

AN:

358868

Other (OTH)

AF:

0.00

AC:

AN:

24088

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

3.7

PromoterAI

-0.017

Neutral

(source)

Splicing

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.

rs13306560

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