1-11827246-A-G

Variant names:

• chr1-11827246-A-G
• rs7537765
• NM_001286.5:c.840+25A>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.840+25A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,599,422 control chromosomes in the GnomAD database, including 21,136 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 0.17 (2428 hom., cov: 30)
  • Exomes 𝑓: 0.16 (18708 hom.)
• Consequence: CLCN6 NM_001286.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.204
• Publications: 36 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN6	NM_001286.5	c.840+25A>G		intron_variant	Intron 10 of 22	ENST00000346436.11	NP_001277.2
CLCN6	NM_001256959.2	c.774+25A>G		intron_variant	Intron 9 of 21		NP_001243888.2
CLCN6	NR_046428.2	n.896+25A>G		intron_variant	Intron 10 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN6	ENST00000346436.11	c.840+25A>G		intron_variant	Intron 10 of 22	1	NM_001286.5	ENSP00000234488.9

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26174 AN: 151518 Hom.: 2423 Cov.: 30

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.0846

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.0969

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.151

GnomAD2 exomes AF: 0.149 AC: 36772 AN: 246508 AF XY: 0.150

Gnomad AFR exome AF: 0.237

Gnomad AMR exome AF: 0.0943

Gnomad ASJ exome AF: 0.0942

Gnomad EAS exome AF: 0.123

Gnomad FIN exome AF: 0.148

Gnomad NFE exome AF: 0.153

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.158 AC: 229026 AN: 1447786 Hom.: 18708 Cov.: 31 AF XY: 0.158 AC XY: 113673 AN XY: 718528

African (AFR) AF: 0.240 AC: 7912 AN: 32996

American (AMR) AF: 0.0982 AC: 4238 AN: 43142

Ashkenazi Jewish (ASJ) AF: 0.0932 AC: 2404 AN: 25786

East Asian (EAS) AF: 0.111 AC: 4364 AN: 39390

South Asian (SAS) AF: 0.182 AC: 15544 AN: 85606

European-Finnish (FIN) AF: 0.144 AC: 7662 AN: 53272

Middle Eastern (MID) AF: 0.161 AC: 861 AN: 5340

European-Non Finnish (NFE) AF: 0.160 AC: 176392 AN: 1102578

Other (OTH) AF: 0.162 AC: 9649 AN: 59676

GnomAD4 genome AF: 0.173 AC: 26210 AN: 151636 Hom.: 2428 Cov.: 30 AF XY: 0.172 AC XY: 12778 AN XY: 74084

African (AFR) AF: 0.235 AC: 9710 AN: 41262

American (AMR) AF: 0.120 AC: 1829 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0969 AC: 336 AN: 3468

East Asian (EAS) AF: 0.125 AC: 643 AN: 5156

South Asian (SAS) AF: 0.198 AC: 944 AN: 4774

European-Finnish (FIN) AF: 0.156 AC: 1641 AN: 10520

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10663 AN: 67898

Other (OTH) AF: 0.155 AC: 326 AN: 2108

Alfa AF: 0.159 Hom.: 8986

Bravo AF: 0.171

Asia WGS AF: 0.169 AC: 586 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.4
DANN	Benign	0.30
PhyloP100		-0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs7537765; hg19: chr1-11887303; COSMIC: COSV56738694; COSMIC: COSV56738694;