chr1-11806987-T-G

Variant names:

• chr1-11806987-T-G
• rs3737964
• NM_001286.5:c.88-144T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001286.5(CLCN6):​c.88-144T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 536,706 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: 32)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: CLCN6 NM_001286.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.32
• Publications: 37 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]

CLCN6 Gene-Disease associations (from GenCC):

• neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN6	NM_001286.5	MANE Select	c.88-144T>G		intron	N/A	NP_001277.2
	CLCN6	NM_001256959.2		c.88-144T>G		intron	N/A	NP_001243888.2
	CLCN6	NR_046428.2		n.160-144T>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN6	ENST00000346436.11	TSL:1 MANE Select	c.88-144T>G		intron	N/A	ENSP00000234488.9
	CLCN6	ENST00000376490.7	TSL:1	n.88-144T>G		intron	N/A
	CLCN6	ENST00000376491.7	TSL:1	n.88-144T>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000186 AC: 1 AN: 536706 Hom.: 0 Cov.: 7 AF XY: 0.00000352 AC XY: 1 AN XY: 283866

African (AFR) AF: 0.00 AC: 0 AN: 14174

American (AMR) AF: 0.00 AC: 0 AN: 23528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15258

East Asian (EAS) AF: 0.00 AC: 0 AN: 31912

South Asian (SAS) AF: 0.00 AC: 0 AN: 49596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39562

Middle Eastern (MID) AF: 0.000289 AC: 1 AN: 3458

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 330122

Other (OTH) AF: 0.00 AC: 0 AN: 29096

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.41
PhyloP100		-4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs3737964; hg19: chr1-11867044;