rs4577050

chr15-34236747-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001365088.1(SLC12A6):c.3003C>T(p.Leu1001=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.667 in 1,607,134 control chromosomes in the GnomAD database, including 360,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (29337 hom., cov: 32)
  • Exomes 𝑓: 0.67 (331296 hom.)
• Consequence: SLC12A6 NM_001365088.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.156

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 15-34236747-G-A is Benign according to our data. Variant chr15-34236747-G-A is described in ClinVar as [Benign]. Clinvar id is 159896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-34236747-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.156 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A6	NM_001365088.1	c.3003C>T	p.Leu1001=	synonymous_variant	23/26	ENST00000354181.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A6	ENST00000354181.8	c.3003C>T	p.Leu1001=	synonymous_variant	23/26	1	NM_001365088.1	A1

Frequencies

GnomAD3 genomes AF: 0.611 AC: 92826 AN: 151918 Hom.: 29338 Cov.: 32

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.690

Gnomad ASJ AF: 0.628

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.715

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.640

GnomAD3 exomes AF: 0.658 AC: 165521 AN: 251420 Hom.: 55282 AF XY: 0.660 AC XY: 89611 AN XY: 135876

Gnomad AFR exome AF: 0.428

Gnomad AMR exome AF: 0.702

Gnomad ASJ exome AF: 0.624

Gnomad EAS exome AF: 0.675

Gnomad SAS exome AF: 0.609

Gnomad FIN exome AF: 0.716

Gnomad NFE exome AF: 0.681

Gnomad OTH exome AF: 0.650

GnomAD4 exome AF: 0.673 AC: 978619 AN: 1455098 Hom.: 331296 Cov.: 32 AF XY: 0.671 AC XY: 485974 AN XY: 724248

Gnomad4 AFR exome AF: 0.413

Gnomad4 AMR exome AF: 0.698

Gnomad4 ASJ exome AF: 0.623

Gnomad4 EAS exome AF: 0.721

Gnomad4 SAS exome AF: 0.609

Gnomad4 FIN exome AF: 0.709

Gnomad4 NFE exome AF: 0.684

Gnomad4 OTH exome AF: 0.650

GnomAD4 genome AF: 0.611 AC: 92866 AN: 152036 Hom.: 29337 Cov.: 32 AF XY: 0.614 AC XY: 45631 AN XY: 74306

Gnomad4 AFR AF: 0.432

Gnomad4 AMR AF: 0.690

Gnomad4 ASJ AF: 0.628

Gnomad4 EAS AF: 0.671

Gnomad4 SAS AF: 0.603

Gnomad4 FIN AF: 0.715

Gnomad4 NFE AF: 0.681

Gnomad4 OTH AF: 0.641

Alfa AF: 0.656 Hom.: 42698

Bravo AF: 0.602

Asia WGS AF: 0.637 AC: 2215 AN: 3478

EpiCase AF: 0.673

EpiControl AF: 0.671

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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.	Sep 16, 2020	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 06, 2017	Variant summary: The SLC12A6 c.3003C>T (p.Leu1001Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. This variant was found in 79011/121370 control chromosomes (26234 homozygotes) at a frequency of 0.6509928, which is approximately 26 times the estimated maximal expected allele frequency of a pathogenic SLC12A6 variant (0.025), strong evidence that this variant is a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	5.0
Dann	Benign	0.74

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: rs4577050; hg19: chr15-34528948; COSMIC: COSV51626112; COSMIC: COSV51626112;