1-11816605-G-A

Variant names:

• chr1-11816605-G-A
• rs17376328
• NM_001286.5:c.214-10G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001286.5(CLCN6):​c.214-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0498 in 1,610,052 control chromosomes in the GnomAD database, including 2,260 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (191 hom., cov: 33)
  • Exomes 𝑓: 0.050 (2069 hom.)
• Consequence: CLCN6 NM_001286.5 intron
• Scores: Splicing: ADA: 0.0004344
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.69
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 1-11816605-G-A is Benign according to our data. Variant chr1-11816605-G-A is described in ClinVar as Benign. ClinVar VariationId is 1601467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0535 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.214-10G>A		intron	N/A	NP_001277.2
	CLCN6	NM_001256959.2		c.148-10G>A		intron	N/A	NP_001243888.2
	CLCN6	NR_046428.2		n.286-10G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN6	ENST00000346436.11	TSL:1 MANE Select	c.214-10G>A		intron	N/A	ENSP00000234488.9
	CLCN6	ENST00000376490.7	TSL:1	n.214-10G>A		intron	N/A
	CLCN6	ENST00000376491.7	TSL:1	n.214-10G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0437 AC: 6648 AN: 152154 Hom.: 191 Cov.: 33

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0431

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0549

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.0434 AC: 10744 AN: 247304 AF XY: 0.0446

Gnomad AFR exome AF: 0.0226

Gnomad AMR exome AF: 0.0172

Gnomad ASJ exome AF: 0.0127

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.100

Gnomad NFE exome AF: 0.0536

Gnomad OTH exome AF: 0.0397

GnomAD4 exome AF: 0.0505 AC: 73614 AN: 1457780 Hom.: 2069 Cov.: 30 AF XY: 0.0504 AC XY: 36535 AN XY: 725064

African (AFR) AF: 0.0257 AC: 859 AN: 33422

American (AMR) AF: 0.0176 AC: 782 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 335 AN: 26026

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39606

South Asian (SAS) AF: 0.0449 AC: 3843 AN: 85678

European-Finnish (FIN) AF: 0.0932 AC: 4953 AN: 53116

Middle Eastern (MID) AF: 0.0229 AC: 132 AN: 5762

European-Non Finnish (NFE) AF: 0.0542 AC: 60088 AN: 1109556

Other (OTH) AF: 0.0435 AC: 2617 AN: 60224

GnomAD4 genome AF: 0.0437 AC: 6647 AN: 152272 Hom.: 191 Cov.: 33 AF XY: 0.0456 AC XY: 3396 AN XY: 74450

African (AFR) AF: 0.0260 AC: 1081 AN: 41550

American (AMR) AF: 0.0197 AC: 302 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.0427 AC: 206 AN: 4826

European-Finnish (FIN) AF: 0.111 AC: 1173 AN: 10596

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0549 AC: 3736 AN: 68024

Other (OTH) AF: 0.0298 AC: 63 AN: 2116

Alfa AF: 0.0464 Hom.: 338

Bravo AF: 0.0358

Asia WGS AF: 0.0150 AC: 54 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.1
DANN	Benign	0.75
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00043
dbscSNV1_RF	Benign	0.13
SpliceAI score (max)		0.020		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: rs17376328; hg19: chr1-11876662; COSMIC: COSV56743999;