NM_001286.5:c.2529+316G>T

Variant names:

• chr1-11838976-G-T
• rs1023252
• NM_001286.5:c.2529+316G>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.2529+316G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 694,878 control chromosomes in the GnomAD database, including 24,531 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 0.24 (4411 hom., cov: 33)
  • Exomes 𝑓: 0.27 (20120 hom.)
• Consequence: CLCN6 NM_001286.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.846
• Publications: 64 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 (MetaRNN=0.0015443265).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN6	NM_001286.5	c.2529+316G>T		intron_variant	Intron 22 of 22	ENST00000346436.11	NP_001277.2
CLCN6	NM_001256959.2	c.2463+316G>T		intron_variant	Intron 21 of 21		NP_001243888.2
CLCN6	NR_046428.2	n.2585+316G>T		intron_variant	Intron 22 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN6	ENST00000346436.11	c.2529+316G>T		intron_variant	Intron 22 of 22	1	NM_001286.5	ENSP00000234488.9
CLCN6	ENST00000376496.4	c.2845G>T	p.Asp949Tyr	missense_variant	Exon 22 of 22	5		ENSP00000365679.3
CLCN6	ENST00000312413.10	c.2463+316G>T		intron_variant	Intron 21 of 21	2		ENSP00000308367.7
CLCN6	ENST00000400892.3	n.*1022+316G>T		intron_variant	Intron 22 of 26	3		ENSP00000496938.1

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35733 AN: 152006 Hom.: 4411 Cov.: 33

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.232

GnomAD2 exomes AF: 0.256 AC: 37382 AN: 146004 AF XY: 0.266

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.242

Gnomad EAS exome AF: 0.225

Gnomad FIN exome AF: 0.284

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.252

GnomAD4 exome AF: 0.266 AC: 144507 AN: 542754 Hom.: 20120 Cov.: 0 AF XY: 0.274 AC XY: 79075 AN XY: 288874

African (AFR) AF: 0.170 AC: 2612 AN: 15336

American (AMR) AF: 0.147 AC: 4950 AN: 33620

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 4577 AN: 19532

East Asian (EAS) AF: 0.197 AC: 6195 AN: 31482

South Asian (SAS) AF: 0.372 AC: 23040 AN: 62000

European-Finnish (FIN) AF: 0.279 AC: 13211 AN: 47330

Middle Eastern (MID) AF: 0.258 AC: 1030 AN: 4000

European-Non Finnish (NFE) AF: 0.271 AC: 81181 AN: 299786

Other (OTH) AF: 0.260 AC: 7711 AN: 29668

GnomAD4 genome AF: 0.235 AC: 35759 AN: 152124 Hom.: 4411 Cov.: 33 AF XY: 0.236 AC XY: 17545 AN XY: 74350

African (AFR) AF: 0.174 AC: 7209 AN: 41494

American (AMR) AF: 0.172 AC: 2621 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 802 AN: 3472

East Asian (EAS) AF: 0.220 AC: 1136 AN: 5170

South Asian (SAS) AF: 0.363 AC: 1751 AN: 4824

European-Finnish (FIN) AF: 0.294 AC: 3109 AN: 10564

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18340 AN: 68002

Other (OTH) AF: 0.232 AC: 490 AN: 2114

Alfa AF: 0.256 Hom.: 18363

Bravo AF: 0.221

TwinsUK AF: 0.274 AC: 1016

ALSPAC AF: 0.273 AC: 1052

ExAC AF: 0.210 AC: 6423

Asia WGS AF: 0.285 AC: 991 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.47
DANN	Benign	0.82
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.85
PROVEAN	Benign	0.49	N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D
Vest4		0.070
ClinPred		0.0035	T
GERP RS		-6.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1023252; hg19: chr1-11899033; COSMIC: COSV56738706; COSMIC: COSV56738706;