rs121908429

Positions:

chr15-34257713-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM5PP2PP3_StrongPP5

The NM_001365088.1(SLC12A6):c.619C>T(p.Arg207Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000559 in 1,609,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R207H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SLC12A6
NM_001365088.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 5.56

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-34257712-C-T is described in Lovd as [Pathogenic].

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 15-34257713-G-A is Pathogenic according to our data. Variant chr15-34257713-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5331.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1}. Variant chr15-34257713-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A6	NM_001365088.1 linkuse as main transcript	c.619C>T	p.Arg207Cys	missense_variant	6/26	ENST00000354181.8	NP_001352017.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A6	ENST00000354181.8 linkuse as main transcript	c.619C>T	p.Arg207Cys	missense_variant	6/26	1	NM_001365088.1	ENSP00000346112	A1	Q9UHW9-1
	ENST00000559867.1 linkuse as main transcript	n.268G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251302

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000549

AC:

AN:

1457850

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725558

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000632

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152050

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Agenesis of the corpus callosum with peripheral neuropathy

Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 12, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Center for Molecular Medicine, Children’s Hospital of Fudan University	Feb 08, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 10, 2021	The SLC12A6 c.619C>T (p.Arg207Cys) missense variant results in the substitution of arginine at amino acid position 207 with cysteine. This variant has been reported in a homozygous state in one individual presenting with complete agenesis of the corpus callosum, demyelinating neuropathy, dysmorphism and psychomotor retardation (Uyanik et al. 2006). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000054 in the East Asian population (version 2.1.1). A different missense change at the same position, c.620G>A (p.Arg207His), has been noted in two individuals affected with early-onset progressive sensorimotor neuropathy in a heterozygous state and of de novo origin (Park et al. 2020). The Arg207Cys variant protein when expressed in Xenopus oocytes showed significantly reduced K+ influx compared to wild-type, suggestive of impaired potassium-chloride transport (Salin-Cantegrel et al. 2011; Park et al. 2020). Further, the Arg207Cys protein was mislocalized to the perinucleus instead of the plasma membrane in HeLa and PC12 cells (Salin-Cantegrel et al. 2011). Based on the available evidence, the c.619C>T (p.Arg207Cys) variant is classified as likely pathogenic for agenesis of the corpus callosum with peripheral neuropathy. -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 23, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 207 of the SLC12A6 protein (p.Arg207Cys). This variant is present in population databases (rs121908429, gnomAD 0.006%). This missense change has been observed in individual(s) with agenesis of the corpus callosum with peripheral neuropathy (PMID: 16606917). ClinVar contains an entry for this variant (Variation ID: 5331). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC12A6 protein function. Experimental studies have shown that this missense change affects SLC12A6 function (PMID: 21628467). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

.;.;D;D;.;.;D;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

D;D;.;.;.;D;D;D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.2

.;.;H;H;.;.;H;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A;A

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.3

D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D

Polyphen

1.0

.;D;D;D;.;.;D;.;.

Vest4

0.95

MutPred

0.93

.;.;Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;.;Loss of helix (P = 0.1299);.;.;

MVP

0.97

MPC

1.2

ClinPred

1.0

GERP RS

5.5

Varity_R

0.78

gMVP

0.97

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

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