rs1057520062

Positions:

chr15-34250333-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001365088.1(SLC12A6):c.1614T>G(p.Phe538Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000126 in 1,591,526 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

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

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SLC12A6
NM_001365088.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.02

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A6	NM_001365088.1 linkuse as main transcript	c.1614T>G	p.Phe538Leu	missense_variant	13/26	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.1614T>G	p.Phe538Leu	missense_variant	13/26	1	NM_001365088.1	ENSP00000346112	A1	Q9UHW9-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152244

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

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1439282

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717464

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.16e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74388

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:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 30, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2022	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. 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 not expected to disrupt SLC12A6 protein function. ClinVar contains an entry for this variant (Variation ID: 376809). This variant has not been reported in the literature in individuals affected with SLC12A6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 538 of the SLC12A6 protein (p.Phe538Leu). -

Agenesis of the corpus callosum with peripheral neuropathy

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

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

Eigen

Benign

0.021

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

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

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.58

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.3

.;.;L;L;.;.;.;L;.

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.4

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

REVEL

Pathogenic

0.74

Sift

Benign

0.055

T;D;D;D;T;T;D;D;D

Sift4G

Benign

0.065

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

Polyphen

0.49, 0.085, 0.034

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

Vest4

0.62

MutPred

0.56

.;.;Loss of catalytic residue at G539 (P = 0.2538);Loss of catalytic residue at G539 (P = 0.2538);.;.;.;Loss of catalytic residue at G539 (P = 0.2538);.;

MVP

0.81

MPC

1.1

ClinPred

0.99

GERP RS

5.0

Varity_R

0.67

gMVP

0.85

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