NM_001365088.1:c.619C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM5PP3_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. 13/22 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

Publications

8 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:

ENSG00000259468 (HGNC:):

ENSG00000259468 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-34257712-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 521402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 VariationId is 5331.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A6	NM_001365088.1 link	c.619C>T	p.Arg207Cys	missense_variant	Exon 6 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.619C>T	p.Arg207Cys	missense_variant	Exon 6 of 26	1	NM_001365088.1	ENSP00000346112.3

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

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251302

AF XY:

0.00000736

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 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

African (AFR)

AF:

0.00

AC:

AN:

33386

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000632

AC:

AN:

1108376

Other (OTH)

AF:

0.00

AC:

AN:

60246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000658

AC:

AN:

152050

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41390

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

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

Jul 15, 2021

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 08, 2022

Center for Molecular Medicine, Children’s Hospital of Fudan University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 01, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 12, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Dec 10, 2021

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Inherited Neuropathy Consortium

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

not provided

Uncertain:1

Aug 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0

.;.;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

Benign

0.0

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

PhyloP100

5.6

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

Vest4

0.95

ClinPred

1.0

GERP RS

5.5

Varity_R

0.78

gMVP

0.97

Mutation Taster

=2/98

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over