Genetic Variant NM_001286.5:c.*545G>T (chr1-11840768-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001286.5(CLCN6):c.*545G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 171,272 control chromosomes in the GnomAD database, including 3,916 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 0.19 ( 3745 hom., cov: 33)

Exomes 𝑓: 0.12 ( 171 hom. )

Consequence

CLCN6
NM_001286.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.22

Publications

25 publications found

Variant links:

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 links:

NPPA-AS1 (HGNC:37635): (NPPA antisense RNA 1)

NPPA-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CLCN6	NM_001286.5 link	c.*545G>T	3_prime_UTR_variant	Exon 23 of 23	ENST00000346436.11	NP_001277.2	P51797-1
NPPA-AS1	NR_037806.1 link	n.450G>T	non_coding_transcript_exon_variant	Exon 1 of 4
CLCN6	NR_046428.2 link	n.3211G>T	non_coding_transcript_exon_variant	Exon 23 of 23
CLCN6	NM_001256959.2 link	c.*545G>T	3_prime_UTR_variant	Exon 22 of 22		NP_001243888.2	P51797-6

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLCN6	ENST00000346436.11 link	c.*545G>T	3_prime_UTR_variant	Exon 23 of 23	1	NM_001286.5	ENSP00000234488.9	P51797-1
CLCN6	ENST00000312413.10 link	c.*545G>T	3_prime_UTR_variant	Exon 22 of 22	2		ENSP00000308367.7	P51797-6
CLCN6	ENST00000400892.3 link	n.*1252-290G>T	intron_variant	Intron 23 of 26	3		ENSP00000496938.1	A0A3B3IRY0
CLCN6	ENST00000446542.5 link	n.-249G>T	upstream_gene_variant		1

Frequencies

GnomAD3 genomes

AF:

0.191

AC:

29013

AN:

151962

Hom.:

3739

Cov.:

show subpopulations

Gnomad AFR

AF:

0.364

Gnomad AMI

AF:

0.136

Gnomad AMR

AF:

0.131

Gnomad ASJ

AF:

0.115

Gnomad EAS

AF:

0.0104

Gnomad SAS

AF:

0.144

Gnomad FIN

AF:

0.0723

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.140

Gnomad OTH

AF:

0.189

GnomAD4 exome

AF:

0.121

AC:

2331

AN:

19192

Hom.:

171

Cov.:

AF XY:

0.120

AC XY:

1191

AN XY:

9940

show subpopulations

African (AFR)

AF:

0.323

AC:

298

AN:

922

American (AMR)

AF:

0.105

AC:

316

AN:

3012

Ashkenazi Jewish (ASJ)

AF:

0.0871

AC:

AN:

310

East Asian (EAS)

AF:

0.00828

AC:

AN:

1812

South Asian (SAS)

AF:

0.143

AC:

284

AN:

1982

European-Finnish (FIN)

AF:

0.0719

AC:

AN:

306

Middle Eastern (MID)

AF:

0.250

AC:

AN:

European-Non Finnish (NFE)

AF:

0.125

AC:

1243

AN:

9934

Other (OTH)

AF:

0.133

AC:

117

AN:

878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

100

200

300

400

500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.191

AC:

29044

AN:

152080

Hom.:

3745

Cov.:

AF XY:

0.188

AC XY:

13999

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.363

AC:

15052

AN:

41442

American (AMR)

AF:

0.131

AC:

1997

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.115

AC:

399

AN:

3468

East Asian (EAS)

AF:

0.0104

AC:

AN:

5170

South Asian (SAS)

AF:

0.143

AC:

690

AN:

4818

European-Finnish (FIN)

AF:

0.0723

AC:

765

AN:

10588

Middle Eastern (MID)

AF:

0.245

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.140

AC:

9490

AN:

68002

Other (OTH)

AF:

0.190

AC:

401

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1128

2257

3385

4514

5642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

294

588

882

1176

1470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.154

Hom.:

3591

Bravo

AF:

0.202

Asia WGS

AF:

0.0960

AC:

334

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.62

(source)

DANN

Benign

0.47

PhyloP100

-2.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over