Genetic Variant SLC12A6:p.Ser412Ser (chr15-34252267-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001365088.1(SLC12A6):c.1236G>A(p.Ser412Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,604,754 control chromosomes in the GnomAD database, including 26,099 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. S412S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.17 ( 2169 hom., cov: 31)

Exomes 𝑓: 0.18 ( 23930 hom. )

Consequence

SLC12A6
NM_001365088.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.83

Publications

21 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 15-34252267-C-T is Benign according to our data. Variant chr15-34252267-C-T is described in ClinVar as Benign. ClinVar VariationId is 139119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.83 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 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.1236G>A	p.Ser412Ser	synonymous	Exon 10 of 26	NP_001352017.1	Q9UHW9-1
SLC12A6	NM_133647.2		c.1236G>A	p.Ser412Ser	synonymous	Exon 9 of 25	NP_598408.1	Q9UHW9-1
SLC12A6	NM_001042496.2		c.1209G>A	p.Ser403Ser	synonymous	Exon 10 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.1236G>A	p.Ser412Ser	synonymous	Exon 10 of 26	ENSP00000346112.3	Q9UHW9-1
SLC12A6	ENST00000560611.5	TSL:1	c.1236G>A	p.Ser412Ser	synonymous	Exon 9 of 25	ENSP00000454168.1	Q9UHW9-1
SLC12A6	ENST00000558589.5	TSL:1	c.1209G>A	p.Ser403Ser	synonymous	Exon 10 of 26	ENSP00000452776.1	Q9UHW9-4

Frequencies

GnomAD3 genomes

AF:

0.166

AC:

25209

AN:

151816

Hom.:

2173

Cov.:

show subpopulations

Gnomad AFR

AF:

0.127

Gnomad AMI

AF:

0.177

Gnomad AMR

AF:

0.177

Gnomad ASJ

AF:

0.190

Gnomad EAS

AF:

0.284

Gnomad SAS

AF:

0.225

Gnomad FIN

AF:

0.159

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.173

Gnomad OTH

AF:

0.179

GnomAD2 exomes

AF:

0.188

AC:

47234

AN:

251278

AF XY:

0.190

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.188

Gnomad ASJ exome

AF:

0.184

Gnomad EAS exome

AF:

0.278

Gnomad FIN exome

AF:

0.165

Gnomad NFE exome

AF:

0.176

Gnomad OTH exome

AF:

0.196

GnomAD4 exome

AF:

0.179

AC:

259853

AN:

1452822

Hom.:

23930

Cov.:

AF XY:

0.180

AC XY:

130557

AN XY:

723442

show subpopulations

African (AFR)

AF:

0.127

AC:

4218

AN:

33284

American (AMR)

AF:

0.188

AC:

8395

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.189

AC:

4923

AN:

26064

East Asian (EAS)

AF:

0.250

AC:

9902

AN:

39648

South Asian (SAS)

AF:

0.225

AC:

19356

AN:

86060

European-Finnish (FIN)

AF:

0.172

AC:

9205

AN:

53416

Middle Eastern (MID)

AF:

0.276

AC:

1588

AN:

5744

European-Non Finnish (NFE)

AF:

0.173

AC:

191114

AN:

1103818

Other (OTH)

AF:

0.186

AC:

11152

AN:

60092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

9650

19299

28949

38598

48248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6894

13788

20682

27576

34470

<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:

0.166

AC:

25210

AN:

151932

Hom.:

2169

Cov.:

AF XY:

0.168

AC XY:

12505

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.127

AC:

5254

AN:

41426

American (AMR)

AF:

0.177

AC:

2706

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.190

AC:

660

AN:

3470

East Asian (EAS)

AF:

0.284

AC:

1466

AN:

5162

South Asian (SAS)

AF:

0.225

AC:

1083

AN:

4808

European-Finnish (FIN)

AF:

0.159

AC:

1677

AN:

10538

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.173

AC:

11752

AN:

67956

Other (OTH)

AF:

0.179

AC:

376

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1046

2092

3139

4185

5231

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

290

580

870

1160

1450

<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:

0.168

Hom.:

3576

Bravo

AF:

0.165

Asia WGS

AF:

0.227

AC:

789

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 (4)

Agenesis of the corpus callosum with peripheral neuropathy (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

2.1

(source)

DANN

Benign

0.79

PhyloP100

-1.8

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over