rs35583475

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001365088.1(SLC12A6):c.963C>T(p.Tyr321Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,612,878 control chromosomes in the GnomAD database, including 431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 43 hom., cov: 32)

Exomes 𝑓: 0.017 ( 388 hom. )

Consequence

SLC12A6
NM_001365088.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.594

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:

SLC12A6 (HGNC:):

SLC12A6 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 15-34254503-G-A is Benign according to our data. Variant chr15-34254503-G-A is described in ClinVar as [Benign]. Clinvar id is 139118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-34254503-G-A is described in Lovd as [Benign]. Variant chr15-34254503-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.594 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A6	NM_001365088.1 linkuse as main transcript	c.963C>T	p.Tyr321Tyr	synonymous_variant	9/26	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.963C>T	p.Tyr321Tyr	synonymous_variant	9/26	1	NM_001365088.1	ENSP00000346112.3		Q9UHW9-1

Frequencies

GnomAD3 genomes

AF:

0.0168

AC:

2549

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00403

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0356

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0110

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0712

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0146

Gnomad OTH

AF:

0.0143

GnomAD3 exomes

AF:

0.0257

AC:

6451

AN:

251396

Hom.:

195

AF XY:

0.0231

AC XY:

3142

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.0798

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.0127

Gnomad SAS exome

AF:

0.00160

Gnomad FIN exome

AF:

0.0702

Gnomad NFE exome

AF:

0.0148

Gnomad OTH exome

AF:

0.0248

GnomAD4 exome

AF:

0.0169

AC:

24715

AN:

1460612

Hom.:

388

Cov.:

AF XY:

0.0163

AC XY:

11812

AN XY:

726744

show subpopulations

Gnomad4 AFR exome

AF:

0.00221

Gnomad4 AMR exome

AF:

0.0735

Gnomad4 ASJ exome

AF:

0.000727

Gnomad4 EAS exome

AF:

0.0124

Gnomad4 SAS exome

AF:

0.00161

Gnomad4 FIN exome

AF:

0.0654

Gnomad4 NFE exome

AF:

0.0146

Gnomad4 OTH exome

AF:

0.0170

GnomAD4 genome

AF:

0.0168

AC:

2555

AN:

152266

Hom.:

Cov.:

AF XY:

0.0192

AC XY:

1431

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00402

Gnomad4 AMR

AF:

0.0359

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0108

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0712

Gnomad4 NFE

AF:

0.0146

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.0131

Hom.:

Bravo

AF:

0.0161

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0105

EpiControl

AF:

0.0120

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Agenesis of the corpus callosum with peripheral neuropathy

Benign:3

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

9.2

DANN

Benign

0.87

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