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. Variant got -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. 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

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 Likely_benign. Variant got -5 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN6	NM_001286.5	c.37_54dupAGGTGGTGCTGCTGCTGC	p.Arg13_Cys18dup	conservative_inframe_insertion	Exon 1 of 23	ENST00000346436.11	NP_001277.2
CLCN6	NM_001256959.2	c.37_54dupAGGTGGTGCTGCTGCTGC	p.Arg13_Cys18dup	conservative_inframe_insertion	Exon 1 of 22		NP_001243888.2
CLCN6	NR_046428.2	n.109_126dupAGGTGGTGCTGCTGCTGC		non_coding_transcript_exon_variant	Exon 1 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN6	ENST00000346436.11	c.37_54dupAGGTGGTGCTGCTGCTGC	p.Arg13_Cys18dup	conservative_inframe_insertion	Exon 1 of 23	1	NM_001286.5	ENSP00000234488.9

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

GnomAD3 exomes AF: 0.0000906 AC: 14 AN: 154454 Hom.: 0 AF XY: 0.000126 AC XY: 11 AN XY: 87596

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 SAS exome AF: 0.000325

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

Gnomad4 AFR exome AF: 0.000340

Gnomad4 AMR exome AF: 0.000145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000631

Gnomad4 SAS exome AF: 0.000493

Gnomad4 FIN exome AF: 0.000214

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.0000720

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

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.37_54dup, results in the insertion of 6 amino acid(s) of the CLCN6 protein (p.Arg13_Cys18dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs754787159, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CLCN6-related conditions. ClinVar contains an entry for this variant (Variation ID: 1498230). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs754787159; hg19: chr1-11866342;