1-11806126-C-A

Variant names:

• chr1-11806126-C-A
• rs13306560
• ENST00000312413.10:c.-137C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000312413.10(CLCN6):​c.-137C>A variant causes a 5 prime UTR 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: CLCN6 ENST00000312413.10 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.66
• Publications: 0 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: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000312413.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN6	NM_001286.5	MANE Select	c.-137C>A		upstream_gene	N/A	NP_001277.2	P51797-1
	MTHFR	NM_005957.5	MANE Select	c.-252G>T		upstream_gene	N/A	NP_005948.3
	CLCN6	NM_001256959.2		c.-137C>A		upstream_gene	N/A	NP_001243888.2	P51797-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN6	ENST00000312413.10	TSL:2	c.-137C>A		5_prime_UTR	Exon 1 of 22	ENSP00000308367.7	P51797-6
	MTHFR	ENST00000911085.1		c.-790G>T		5_prime_UTR	Exon 1 of 12	ENSP00000581144.1
	MTHFR	ENST00000641747.1		n.-252G>T		non_coding_transcript_exon	Exon 1 of 11	ENSP00000493116.1	A0A286YF47

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 1 AN: 487976 Hom.: 0 Cov.: 7 AF XY: 0.00000412 AC XY: 1 AN XY: 242684

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

African (AFR) AF: 0.00 AC: 0 AN: 11146

American (AMR) AF: 0.00 AC: 0 AN: 7738

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10704

East Asian (EAS) AF: 0.00 AC: 0 AN: 23838

South Asian (SAS) AF: 0.00 AC: 0 AN: 14174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3096

European-Non Finnish (NFE) AF: 0.00000279 AC: 1 AN: 358868

Other (OTH) AF: 0.00 AC: 0 AN: 24088

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Benign	0.94
PhyloP100		3.7
PromoterAI		-0.017	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs13306560; hg19: chr1-11866183;