chr15-34250671-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001365088.1(SLC12A6):c.1551G>C(p.Pro517Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,599,874 control chromosomes in the GnomAD database, including 25,941 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P517P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.17 ( 2188 hom., cov: 32)

Exomes 𝑓: 0.18 ( 23753 hom. )

Consequence

SLC12A6
NM_001365088.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.174

Publications

20 publications found

Variant links:

Genes affected

SLC12A6 (HGNC:10914): (solute carrier family 12 member 6) This gene is a member of the K-Cl cotransporter (KCC) family. K-Cl cotransporters are integral membrane proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The proteins encoded by this gene are activated by cell swelling induced by hypotonic conditions. Alternate splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are associated with agenesis of the corpus callosum with peripheral neuropathy. [provided by RefSeq, Jul 2008]

SLC12A6 Gene-Disease associations (from GenCC):

agenesis of the corpus callosum with peripheral neuropathy
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
Charcot-Marie-Tooth disease, axonal, IIa 2II
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

SLC12A6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 15-34250671-C-G is Benign according to our data. Variant chr15-34250671-C-G is described in ClinVar as Benign. ClinVar VariationId is 139121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.174 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A6	NM_001365088.1 link	c.1551G>C	p.Pro517Pro	synonymous_variant	Exon 12 of 26	ENST00000354181.8	NP_001352017.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A6	ENST00000354181.8 link	c.1551G>C	p.Pro517Pro	synonymous_variant	Exon 12 of 26	1	NM_001365088.1	ENSP00000346112.3

Frequencies

GnomAD3 genomes

AF:

0.167

AC:

25369

AN:

151982

Hom.:

2193

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.177

Gnomad AMR

AF:

0.178

Gnomad ASJ

AF:

0.191

Gnomad EAS

AF:

0.286

Gnomad SAS

AF:

0.226

Gnomad FIN

AF:

0.158

Gnomad MID

AF:

0.268

Gnomad NFE

AF:

0.173

Gnomad OTH

AF:

0.181

GnomAD2 exomes

AF:

0.189

AC:

47439

AN:

251268

AF XY:

0.191

show subpopulations

Gnomad AFR exome

AF:

0.126

Gnomad AMR exome

AF:

0.190

Gnomad ASJ exome

AF:

0.184

Gnomad EAS exome

AF:

0.282

Gnomad FIN exome

AF:

0.166

Gnomad NFE exome

AF:

0.177

Gnomad OTH exome

AF:

0.196

GnomAD4 exome

AF:

0.178

AC:

257555

AN:

1447774

Hom.:

23753

Cov.:

AF XY:

0.180

AC XY:

129571

AN XY:

721100

show subpopulations

African (AFR)

AF:

0.129

AC:

4276

AN:

33248

American (AMR)

AF:

0.189

AC:

8468

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.188

AC:

4896

AN:

26028

East Asian (EAS)

AF:

0.251

AC:

9955

AN:

39612

South Asian (SAS)

AF:

0.225

AC:

19321

AN:

85944

European-Finnish (FIN)

AF:

0.173

AC:

9216

AN:

53412

Middle Eastern (MID)

AF:

0.276

AC:

1587

AN:

5740

European-Non Finnish (NFE)

AF:

0.172

AC:

188779

AN:

1099232

Other (OTH)

AF:

0.185

AC:

11057

AN:

59860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

10461

20922

31382

41843

52304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6774

13548

20322

27096

33870

<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:

0.167

AC:

25370

AN:

152100

Hom.:

2188

Cov.:

AF XY:

0.169

AC XY:

12591

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.129

AC:

5362

AN:

41492

American (AMR)

AF:

0.178

AC:

2724

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.191

AC:

661

AN:

3466

East Asian (EAS)

AF:

0.286

AC:

1474

AN:

5160

South Asian (SAS)

AF:

0.227

AC:

1092

AN:

4818

European-Finnish (FIN)

AF:

0.158

AC:

1675

AN:

10576

Middle Eastern (MID)

AF:

0.257

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.173

AC:

11766

AN:

67978

Other (OTH)

AF:

0.180

AC:

380

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1091

2182

3272

4363

5454

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

292

584

876

1168

1460

<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:

0.117

Hom.:

253

Bravo

AF:

0.166

Asia WGS

AF:

0.229

AC:

796

AN:

3478

EpiCase

AF:

0.182

EpiControl

AF:

0.185

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 28, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 14, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Agenesis of the corpus callosum with peripheral neuropathy

Benign:4

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.71

PhyloP100

-0.17

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over