1-11829411-A-G

Variant names:

• chr1-11829411-A-G
• rs535107
• NM_001286.5:c.1248+89A>G

Variant summary

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

The NM_001286.5(CLCN6):​c.1248+89A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 1,473,160 control chromosomes in the GnomAD database, including 129,885 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 0.43 (14821 hom., cov: 32)
  • Exomes 𝑓: 0.41 (115064 hom.)
• Consequence: CLCN6 NM_001286.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0700
• Publications: 21 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.535 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN6	NM_001286.5	MANE Select	c.1248+89A>G		intron	N/A	NP_001277.2
	CLCN6	NM_001256959.2		c.1182+89A>G		intron	N/A	NP_001243888.2
	CLCN6	NR_046428.2		n.1304+89A>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.1248+89A>G		intron	N/A	ENSP00000234488.9
	CLCN6	ENST00000376496.4	TSL:5	c.1248+89A>G		intron	N/A	ENSP00000365679.3
	CLCN6	ENST00000312413.10	TSL:2	c.1182+89A>G		intron	N/A	ENSP00000308367.7

Frequencies

GnomAD3 genomes AF: 0.432 AC: 65669 AN: 151964 Hom.: 14808 Cov.: 32

Gnomad AFR AF: 0.541

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.360

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.418

Gnomad OTH AF: 0.429

GnomAD4 exome AF: 0.411 AC: 542722 AN: 1321078 Hom.: 115064 AF XY: 0.415 AC XY: 274203 AN XY: 660396

African (AFR) AF: 0.543 AC: 16628 AN: 30630

American (AMR) AF: 0.238 AC: 10242 AN: 43006

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 8672 AN: 23814

East Asian (EAS) AF: 0.213 AC: 8239 AN: 38646

South Asian (SAS) AF: 0.525 AC: 42042 AN: 80126

European-Finnish (FIN) AF: 0.358 AC: 18373 AN: 51382

Middle Eastern (MID) AF: 0.516 AC: 2515 AN: 4878

European-Non Finnish (NFE) AF: 0.416 AC: 413070 AN: 993242

Other (OTH) AF: 0.414 AC: 22941 AN: 55354

GnomAD4 genome AF: 0.432 AC: 65723 AN: 152082 Hom.: 14821 Cov.: 32 AF XY: 0.430 AC XY: 31966 AN XY: 74322

African (AFR) AF: 0.541 AC: 22431 AN: 41478

American (AMR) AF: 0.305 AC: 4663 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.360 AC: 1249 AN: 3470

East Asian (EAS) AF: 0.231 AC: 1200 AN: 5184

South Asian (SAS) AF: 0.508 AC: 2448 AN: 4822

European-Finnish (FIN) AF: 0.369 AC: 3903 AN: 10568

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.418 AC: 28403 AN: 67956

Other (OTH) AF: 0.430 AC: 909 AN: 2114

Alfa AF: 0.411 Hom.: 6670

Bravo AF: 0.429

Asia WGS AF: 0.383 AC: 1330 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.5
DANN	Benign	0.40
PhyloP100		-0.070
Mutation Taster		=99/1	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: rs535107; hg19: chr1-11889468; COSMIC: COSV56738838; COSMIC: COSV56738838;