chr1-11806126-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BA1

The ENST00000312413.10(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 ENST00000312413.10 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.66
• Publications: 23 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: 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 VariationId 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.

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>T		upstream_gene	N/A	NP_001277.2	P51797-1
	MTHFR	NM_005957.5	MANE Select	c.-252G>A		upstream_gene	N/A	NP_005948.3
	CLCN6	NM_001256959.2		c.-137C>T		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>T		5_prime_UTR	Exon 1 of 22	ENSP00000308367.7	P51797-6
	MTHFR	ENST00000911085.1		c.-790G>A		5_prime_UTR	Exon 1 of 12	ENSP00000581144.1
	MTHFR	ENST00000641747.1		n.-252G>A		non_coding_transcript_exon	Exon 1 of 11	ENSP00000493116.1	A0A286YF47

Frequencies

GnomAD3 genomes AF: 0.0371 AC: 5643 AN: 152200 Hom.: 151 Cov.: 33

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.: 7 AF XY: 0.0483 AC XY: 11711 AN XY: 242544

African (AFR) AF: 0.0115 AC: 128 AN: 11146

American (AMR) AF: 0.0339 AC: 262 AN: 7736

Ashkenazi Jewish (ASJ) AF: 0.0506 AC: 541 AN: 10702

East Asian (EAS) AF: 0.00583 AC: 139 AN: 23838

South Asian (SAS) AF: 0.0380 AC: 538 AN: 14166

European-Finnish (FIN) AF: 0.0328 AC: 1125 AN: 34314

Middle Eastern (MID) AF: 0.115 AC: 356 AN: 3094

European-Non Finnish (NFE) AF: 0.0538 AC: 19289 AN: 358646

Other (OTH) AF: 0.0456 AC: 1097 AN: 24080

GnomAD4 genome AF: 0.0371 AC: 5648 AN: 152318 Hom.: 153 Cov.: 33 AF XY: 0.0371 AC XY: 2762 AN XY: 74480

African (AFR) AF: 0.0109 AC: 454 AN: 41580

American (AMR) AF: 0.0404 AC: 618 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0542 AC: 188 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5182

South Asian (SAS) AF: 0.0421 AC: 203 AN: 4824

European-Finnish (FIN) AF: 0.0316 AC: 336 AN: 10622

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0542 AC: 3689 AN: 68018

Other (OTH) AF: 0.0449 AC: 95 AN: 2114

Alfa AF: 0.0487 Hom.: 255

Bravo AF: 0.0363

Asia WGS AF: 0.0310 AC: 109 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Homocystinuria due to methylene tetrahydrofolate reductase deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Benign	0.95
PhyloP100		3.7
PromoterAI		-0.024	Neutral
Mutation Taster		=99/1	polymorphism

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; COSMIC: COSV56742790; COSMIC: COSV56742790;