NM_001286.5:c.148-2034G>T

Variant names:

• chr1-11813812-G-T
• rs12404124
• NM_001286.5:c.148-2034G>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.148-2034G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 151,950 control chromosomes in the GnomAD database, including 24,966 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 0.57 (24966 hom., cov: 33)
• Consequence: CLCN6 NM_001286.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.566
• Publications: 26 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.749 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.148-2034G>T		intron	N/A	NP_001277.2	P51797-1
	CLCN6	NM_001256959.2		c.148-2803G>T		intron	N/A	NP_001243888.2	P51797-6
	CLCN6	NR_046428.2		n.220-2034G>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.148-2034G>T		intron	N/A	ENSP00000234488.9	P51797-1
	CLCN6	ENST00000376490.7	TSL:1	n.148-2034G>T		intron	N/A
	CLCN6	ENST00000376491.7	TSL:1	n.148-2034G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.566 AC: 85967 AN: 151832 Hom.: 24949 Cov.: 33

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.601

Gnomad AMR AF: 0.692

Gnomad ASJ AF: 0.636

Gnomad EAS AF: 0.769

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.630

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.568

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

GnomAD4 genome AF: 0.566 AC: 86030 AN: 151950 Hom.: 24966 Cov.: 33 AF XY: 0.568 AC XY: 42195 AN XY: 74278

African (AFR) AF: 0.454 AC: 18809 AN: 41408

American (AMR) AF: 0.693 AC: 10588 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 2207 AN: 3470

East Asian (EAS) AF: 0.769 AC: 3979 AN: 5176

South Asian (SAS) AF: 0.492 AC: 2374 AN: 4824

European-Finnish (FIN) AF: 0.630 AC: 6638 AN: 10532

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.582 AC: 39555 AN: 67962

Other (OTH) AF: 0.567 AC: 1190 AN: 2098

Alfa AF: 0.558 Hom.: 11277

Bravo AF: 0.569

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.037
DANN	Benign	0.46
PhyloP100		-0.57
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: rs12404124; hg19: chr1-11873869;