rs2075539

Variant names:

• chr1-11837701-G-A
• rs2075539
• NM_001286.5:c.2295+202G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-11837701-G-A
• chr1-11837701-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001286.5(CLCN6):​c.2295+202G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0381 in 152,270 control chromosomes in the GnomAD database, including 190 homozygotes. 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: 𝑓 0.038 (190 hom., cov: 32)
• Consequence: CLCN6 NM_001286.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48
• Publications: 14 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, MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

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.2295+202G>A		intron	N/A	NP_001277.2	P51797-1
	CLCN6	NM_001256959.2		c.2229+202G>A		intron	N/A	NP_001243888.2	P51797-6
	CLCN6	NR_046428.2		n.2351+202G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN6	ENST00000346436.11	TSL:1 MANE Select	c.2295+202G>A		intron	N/A	ENSP00000234488.9	P51797-1
	CLCN6	ENST00000376496.4	TSL:5	c.2295+202G>A		intron	N/A	ENSP00000365679.3	P51797-5
	CLCN6	ENST00000910827.1		c.2355+202G>A		intron	N/A	ENSP00000580886.1

Frequencies

GnomAD3 genomes AF: 0.0382 AC: 5806 AN: 152152 Hom.: 191 Cov.: 32

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0401

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0159

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0467

Gnomad OTH AF: 0.0392

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0381 AC: 5804 AN: 152270 Hom.: 190 Cov.: 32 AF XY: 0.0384 AC XY: 2861 AN XY: 74454

African (AFR) AF: 0.0122 AC: 508 AN: 41574

American (AMR) AF: 0.0398 AC: 608 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.123 AC: 635 AN: 5166

South Asian (SAS) AF: 0.114 AC: 552 AN: 4826

European-Finnish (FIN) AF: 0.0159 AC: 169 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0467 AC: 3177 AN: 68008

Other (OTH) AF: 0.0398 AC: 84 AN: 2112

Alfa AF: 0.0424 Hom.: 62

Bravo AF: 0.0370

Asia WGS AF: 0.111 AC: 383 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Benign	0.83
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2075539; hg19: chr1-11897758;