NM_001286.5:c.37_54dupAGGTGGTGCTGCTGCTGC

Variant names:

• chr1-11806285-T-TGTGCTGCTGCTGCAGGTG
• rs754787159
• NM_001286.5:c.37_54dupAGGTGGTGCTGCTGCTGC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_001286.5(CLCN6):​c.37_54dupAGGTGGTGCTGCTGCTGC​(p.Arg13_Cys18dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000905 in 1,503,256 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: CLCN6 NM_001286.5 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.848
• 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: Likely_benign. The variant received -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001286.5
• BS2: High AC in GnomAd4 at 22 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286.5. 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.37_54dupAGGTGGTGCTGCTGCTGC	p.Arg13_Cys18dup	conservative_inframe_insertion	Exon 1 of 23	NP_001277.2	P51797-1
	CLCN6	NM_001256959.2		c.37_54dupAGGTGGTGCTGCTGCTGC	p.Arg13_Cys18dup	conservative_inframe_insertion	Exon 1 of 22	NP_001243888.2	P51797-6
	CLCN6	NR_046428.2		n.109_126dupAGGTGGTGCTGCTGCTGC		non_coding_transcript_exon	Exon 1 of 23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN6	ENST00000346436.11	TSL:1 MANE Select	c.37_54dupAGGTGGTGCTGCTGCTGC	p.Arg13_Cys18dup	conservative_inframe_insertion	Exon 1 of 23	ENSP00000234488.9	P51797-1
	CLCN6	ENST00000376490.7	TSL:1	n.37_54dupAGGTGGTGCTGCTGCTGC		non_coding_transcript_exon	Exon 1 of 11
	CLCN6	ENST00000376491.7	TSL:1	n.37_54dupAGGTGGTGCTGCTGCTGC		non_coding_transcript_exon	Exon 1 of 11

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000906 AC: 14 AN: 154454 AF XY: 0.000126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000214

Gnomad NFE exome AF: 0.0000510

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000844 AC: 114 AN: 1351004 Hom.: 0 Cov.: 31 AF XY: 0.000103 AC XY: 69 AN XY: 668790

African (AFR) AF: 0.000340 AC: 9 AN: 26438

American (AMR) AF: 0.000145 AC: 3 AN: 20740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22384

East Asian (EAS) AF: 0.0000631 AC: 2 AN: 31688

South Asian (SAS) AF: 0.000493 AC: 34 AN: 69022

European-Finnish (FIN) AF: 0.000214 AC: 11 AN: 51300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5444

European-Non Finnish (NFE) AF: 0.0000477 AC: 51 AN: 1068452

Other (OTH) AF: 0.0000720 AC: 4 AN: 55536

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74442

African (AFR) AF: 0.000193 AC: 8 AN: 41552

American (AMR) AF: 0.000131 AC: 2 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.85
Mutation Taster		=64/36	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs754787159; hg19: chr1-11866342;