Genetic Variant SLC12A6:p.Pro517Pro (chr15-34250671-C-G) – ACMG Classification: Benign (-19 pts)

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: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Orphanet
Charcot-Marie-Tooth disease, axonal, IIa 2II
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365088.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC12A6	NM_001365088.1	MANE Select	c.1551G>C	p.Pro517Pro	synonymous	Exon 12 of 26	NP_001352017.1	Q9UHW9-1
SLC12A6	NM_133647.2		c.1551G>C	p.Pro517Pro	synonymous	Exon 11 of 25	NP_598408.1	Q9UHW9-1
SLC12A6	NM_001042496.2		c.1524G>C	p.Pro508Pro	synonymous	Exon 12 of 26	NP_001035961.1	Q9UHW9-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC12A6	ENST00000354181.8	TSL:1 MANE Select	c.1551G>C	p.Pro517Pro	synonymous	Exon 12 of 26	ENSP00000346112.3	Q9UHW9-1
SLC12A6	ENST00000560611.5	TSL:1	c.1551G>C	p.Pro517Pro	synonymous	Exon 11 of 25	ENSP00000454168.1	Q9UHW9-1
SLC12A6	ENST00000558589.5	TSL:1	c.1524G>C	p.Pro508Pro	synonymous	Exon 12 of 26	ENSP00000452776.1	Q9UHW9-4

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Agenesis of the corpus callosum with peripheral neuropathy (4)

not provided (2)

Computational scores

Source: dbNSFP v4.9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over