rs2075538

Variant names:

• chr1-11836545-T-C
• rs2075538
• NM_001286.5:c.1980+392T>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.1980+392T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 152,108 control chromosomes in the GnomAD database, including 812 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 0.10 (812 hom., cov: 32)
• Consequence: CLCN6 NM_001286.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.24
• Publications: 12 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN6	NM_001286.5	c.1980+392T>C		intron_variant	Intron 18 of 22	ENST00000346436.11	NP_001277.2
CLCN6	NM_001256959.2	c.1914+392T>C		intron_variant	Intron 17 of 21		NP_001243888.2
CLCN6	NR_046428.2	n.2036+392T>C		intron_variant	Intron 18 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN6	ENST00000346436.11	c.1980+392T>C		intron_variant	Intron 18 of 22	1	NM_001286.5	ENSP00000234488.9
CLCN6	ENST00000376496.4	c.1980+392T>C		intron_variant	Intron 18 of 21	5		ENSP00000365679.3
CLCN6	ENST00000312413.10	c.1914+392T>C		intron_variant	Intron 17 of 21	2		ENSP00000308367.7
CLCN6	ENST00000400892.3	n.*473+392T>C		intron_variant	Intron 18 of 26	3		ENSP00000496938.1

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15265 AN: 151990 Hom.: 815 Cov.: 32

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0682

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0838

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

GnomAD4 genome AF: 0.100 AC: 15270 AN: 152108 Hom.: 812 Cov.: 32 AF XY: 0.101 AC XY: 7516 AN XY: 74362

African (AFR) AF: 0.100 AC: 4148 AN: 41498

American (AMR) AF: 0.0678 AC: 1036 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 110 AN: 3470

East Asian (EAS) AF: 0.133 AC: 686 AN: 5174

South Asian (SAS) AF: 0.158 AC: 761 AN: 4808

European-Finnish (FIN) AF: 0.127 AC: 1343 AN: 10584

Middle Eastern (MID) AF: 0.0582 AC: 17 AN: 292

European-Non Finnish (NFE) AF: 0.102 AC: 6948 AN: 67970

Other (OTH) AF: 0.0839 AC: 177 AN: 2110

Alfa AF: 0.0945 Hom.: 325

Bravo AF: 0.0942

Asia WGS AF: 0.132 AC: 457 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.090
DANN	Benign	0.49
PhyloP100		-2.2
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: rs2075538; hg19: chr1-11896602;