1-11812599-C-T

Variant names:

• chr1-11812599-C-T
• rs6687229
• NM_001286.5:c.148-3247C>T

Variant summary

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

The NM_001286.5(CLCN6):​c.148-3247C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0991 in 150,652 control chromosomes in the GnomAD database, including 807 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 0.099 (807 hom., cov: 31)
• Consequence: CLCN6 NM_001286.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.587
• Publications: 8 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=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.147 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.148-3247C>T		intron	N/A	NP_001277.2	P51797-1
	CLCN6	NM_001256959.2		c.148-4016C>T		intron	N/A	NP_001243888.2	P51797-6
	CLCN6	NR_046428.2		n.220-3247C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN6	ENST00000346436.11	TSL:1 MANE Select	c.148-3247C>T		intron	N/A	ENSP00000234488.9	P51797-1
	CLCN6	ENST00000376490.7	TSL:1	n.148-3247C>T		intron	N/A
	CLCN6	ENST00000376491.7	TSL:1	n.148-3247C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0992 AC: 14930 AN: 150534 Hom.: 810 Cov.: 31

Gnomad AFR AF: 0.0982

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0674

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0826

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

GnomAD4 genome AF: 0.0991 AC: 14926 AN: 150652 Hom.: 807 Cov.: 31 AF XY: 0.0998 AC XY: 7332 AN XY: 73444

African (AFR) AF: 0.0980 AC: 4005 AN: 40874

American (AMR) AF: 0.0670 AC: 1015 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 111 AN: 3466

East Asian (EAS) AF: 0.124 AC: 636 AN: 5114

South Asian (SAS) AF: 0.156 AC: 741 AN: 4756

European-Finnish (FIN) AF: 0.126 AC: 1286 AN: 10236

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.102 AC: 6901 AN: 67756

Other (OTH) AF: 0.0827 AC: 173 AN: 2092

Alfa AF: 0.0439 Hom.: 47

Bravo AF: 0.0933

Asia WGS AF: 0.120 AC: 410 AN: 3426

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	5.1
DANN	Benign	0.62
PhyloP100		0.59
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: rs6687229; hg19: chr1-11872656;