1-11806126-C-T

Position:

• chr1-11806126-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN6	ENST00000312413.10	c.-137C>T		5_prime_UTR_variant	1/22	2		ENSP00000308367
MTHFR	ENST00000641747.1	c.-252G>A		5_prime_UTR_variant, NMD_transcript_variant	1/11			ENSP00000493116
MTHFR	ENST00000642002.1			upstream_gene_variant

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

Gnomad4 AFR exome AF: 0.0115

Gnomad4 AMR exome AF: 0.0339

Gnomad4 ASJ exome AF: 0.0506

Gnomad4 EAS exome AF: 0.00583

Gnomad4 SAS exome AF: 0.0380

Gnomad4 FIN exome AF: 0.0328

Gnomad4 NFE exome AF: 0.0538

Gnomad4 OTH exome AF: 0.0456

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

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.0404

Gnomad4 ASJ AF: 0.0542

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0421

Gnomad4 FIN AF: 0.0316

Gnomad4 NFE AF: 0.0542

Gnomad4 OTH AF: 0.0449

Alfa AF: 0.0507 Hom.: 193

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

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Benign	0.95

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs13306560; hg19: chr1-11866183; COSMIC: COSV56742790; COSMIC: COSV56742790;