rs140916001

Positions:

chr15-34250979-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001365088.1(SLC12A6):c.1412G>C(p.Ser471Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00836 in 1,610,528 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S471R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0053 ( 4 hom., cov: 31)

Exomes 𝑓: 0.0087 ( 53 hom. )

Consequence

SLC12A6
NM_001365088.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.0430

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SLC12A6. . Gene score misZ 2.9593 (greater than the threshold 3.09). Trascript score misZ 3.1172 (greater than threshold 3.09). GenCC has associacion of gene with agenesis of the corpus callosum with peripheral neuropathy, Charcot-Marie-Tooth disease, axonal, IIa 2II.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027124584).

BP6

Variant 15-34250979-C-G is Benign according to our data. Variant chr15-34250979-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 284439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-34250979-C-G is described in Lovd as [Benign]. Variant chr15-34250979-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00531 (808/152196) while in subpopulation NFE AF= 0.00891 (606/68002). AF 95% confidence interval is 0.00832. There are 4 homozygotes in gnomad4. There are 355 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A6	NM_001365088.1 linkuse as main transcript	c.1412G>C	p.Ser471Thr	missense_variant	11/26	ENST00000354181.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A6	ENST00000354181.8 linkuse as main transcript	c.1412G>C	p.Ser471Thr	missense_variant	11/26	1	NM_001365088.1	A1	Q9UHW9-1

Frequencies

GnomAD3 genomes

AF:

0.00532

AC:

809

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.00952

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00227

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00893

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00584

AC:

1468

AN:

251476

Hom.:

AF XY:

0.00592

AC XY:

804

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00385

Gnomad ASJ exome

AF:

0.00675

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000817

Gnomad FIN exome

AF:

0.00162

Gnomad NFE exome

AF:

0.00999

Gnomad OTH exome

AF:

0.00847

GnomAD4 exome

AF:

0.00868

AC:

12654

AN:

1458332

Hom.:

Cov.:

AF XY:

0.00845

AC XY:

6136

AN XY:

725786

show subpopulations

Gnomad4 AFR exome

AF:

0.00156

Gnomad4 AMR exome

AF:

0.00394

Gnomad4 ASJ exome

AF:

0.00678

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000847

Gnomad4 FIN exome

AF:

0.00174

Gnomad4 NFE exome

AF:

0.0104

Gnomad4 OTH exome

AF:

0.00951

GnomAD4 genome

AF:

0.00531

AC:

808

AN:

152196

Hom.:

Cov.:

AF XY:

0.00477

AC XY:

355

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.00169

Gnomad4 AMR

AF:

0.00380

Gnomad4 ASJ

AF:

0.00952

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00227

Gnomad4 NFE

AF:

0.00891

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00834

Hom.:

Bravo

AF:

0.00530

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00907

AC:

ExAC

AF:

0.00602

AC:

731

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00932

EpiControl

AF:

0.00901

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:8

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 23, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 18, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SLC12A6: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Agenesis of the corpus callosum with peripheral neuropathy

Benign:4

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2016	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.15

.;.;T;T;.;.;T;T;.

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.72

T;T;.;.;.;T;T;T;T

MetaRNN

Benign

0.0027

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

-0.81

.;.;N;N;.;.;.;N;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

0.090

N;N;N;N;N;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.44

T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.66

T;T;T;T;T;T;T;T;T

Polyphen

0.0010, 0.54, 0.0020

.;B;P;P;.;.;B;P;.

Vest4

0.063

MVP

0.24

MPC

0.29

ClinPred

0.0012

GERP RS

-0.25

Varity_R

0.028

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over