rs7164902

chr15-34258881-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001365088.1(SLC12A6):c.475C>T(p.Leu159=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,611,736 control chromosomes in the GnomAD database, including 48,847 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L159L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.23 (4240 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44607 hom.)
• Consequence: SLC12A6 NM_001365088.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.68

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 15-34258881-G-A is Benign according to our data. Variant chr15-34258881-G-A is described in ClinVar as [Benign]. Clinvar id is 159898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-34258881-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.68 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A6	NM_001365088.1	c.475C>T	p.Leu159=	synonymous_variant	5/26	ENST00000354181.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A6	ENST00000354181.8	c.475C>T	p.Leu159=	synonymous_variant	5/26	1	NM_001365088.1	A1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35590 AN: 151948 Hom.: 4245 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.344

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.220

GnomAD3 exomes AF: 0.247 AC: 62185 AN: 251478 Hom.: 8113 AF XY: 0.253 AC XY: 34362 AN XY: 135918

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.183

Gnomad ASJ exome AF: 0.251

Gnomad EAS exome AF: 0.340

Gnomad SAS exome AF: 0.340

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.243

Gnomad OTH exome AF: 0.246

GnomAD4 exome AF: 0.245 AC: 357005 AN: 1459670 Hom.: 44607 Cov.: 30 AF XY: 0.248 AC XY: 179973 AN XY: 726312

Gnomad4 AFR exome AF: 0.225

Gnomad4 AMR exome AF: 0.185

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.311

Gnomad4 SAS exome AF: 0.340

Gnomad4 FIN exome AF: 0.184

Gnomad4 NFE exome AF: 0.240

Gnomad4 OTH exome AF: 0.251

GnomAD4 genome AF: 0.234 AC: 35612 AN: 152066 Hom.: 4240 Cov.: 32 AF XY: 0.235 AC XY: 17465 AN XY: 74314

Gnomad4 AFR AF: 0.217

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.253

Gnomad4 EAS AF: 0.343

Gnomad4 SAS AF: 0.347

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.221

Alfa AF: 0.247 Hom.: 3987

Bravo AF: 0.232

Asia WGS AF: 0.294 AC: 1022 AN: 3478

EpiCase AF: 0.249

EpiControl AF: 0.245

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Agenesis of the corpus callosum with peripheral neuropathy Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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.	Nov 21, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	8.1
Dann	Benign	0.82

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

Other links and lift over

dbSNP: rs7164902; hg19: chr15-34551082; COSMIC: COSV51631686; COSMIC: COSV51631686;