rs515726215

Positions:

• chr15-34240659-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1_Moderate PP3 PP5_Very_Strong

The NM_001365088.1(SLC12A6):​c.2436+1delG variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,232 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: SLC12A6 NM_001365088.1 splice_donor, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 U:2 O:1
• Conservation: PhyloP100: 7.84

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.048653346 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5, offset of 0 (no position change), new splice context is: gcaGTaaga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP3: Multiple lines of computational evidence support a deleterious effect 2: max_spliceai, phyloP100way_vertebrate [when was below the threshold]
• PP5: Variant 15-34240659-AC-A is Pathogenic according to our data. Variant chr15-34240659-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 436730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-34240659-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A6	NM_001365088.1	c.2436+1delG		splice_donor_variant, intron_variant		ENST00000354181.8	NP_001352017.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A6	ENST00000354181.8	c.2436+1delG		splice_donor_variant, intron_variant		1	NM_001365088.1	ENSP00000346112.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152180 Hom.: 0 Cov.: 32

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251404 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461052 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 726900

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000387

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74338

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Agenesis of the corpus callosum with peripheral neuropathy Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_133647.1(SLC12A6):c.2436+1delG(aka T813fs*813) is classified as pathogenic in the context of Andermann syndrome. Sources cited for classification include the following: PMID 12368912. Classification of NM_133647.1(SLC12A6):c.2436+1delG(aka T813fs*813) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 18, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 12, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 08, 2018	Variant summary: SLC12A6 c.2436+1delG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site, while three predict the variant weakens a 5' donor site. These predictions are supported by a study that found a cryptic splice site is preferentially used in patient cells and the resulting protein product is reduced in size and does not function in chloride dependent uptake of 86Rb+ compared to controls, although it is properly localized and glycosylated (Howard_2002). The variant allele was found at a frequency of 5.4e-05 in 277348 control chromosomes. This frequency is not higher than expected for a pathogenic variant in SLC12A6 causing Andermann Syndrome (5.4e-05 vs 0.025), allowing no conclusion about variant significance. c.2436+1delG has been reported in the literature in numerous homozygous French Canadian individuals affected with Andermann Syndrome. These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 03, 2023	This sequence change creates a premature translational stop signal (Splice site) in the SLC12A6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC12A6 are known to be pathogenic (PMID: 12368912, 16606917). This variant is present in population databases (rs752155285, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with agenesis of the corpus callosum with peripheral neuropathy (PMID: 12368912, 12838516, 17893295). It is commonly reported in individuals of French Canadian ancestry (PMID: 12368912). This variant is also known as c.2436+1del. ClinVar contains an entry for this variant (Variation ID: 436730). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2022	Published functional studies demonstrate a damaging effect resulting in nonfunctional protein (Howard et al., 2002); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20301546, 12368912) -

Agenesis of the corpus callosum with peripheral neuropathy;C5774227:Charcot-Marie-Tooth disease, axonal, IIa 2II Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 04, 2024

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SLC12A6-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 2024

The SLC12A6 c.2436+1delG variant is predicted to result in a deletion affecting a canonical splice site. In the homozygous state, this variant has been documented to be causative for peripheral neuropathy associated with agenesis of the corpus callosum (ACCPN); and was determined to be a founder mutation in the French Canadian population (Howard et al. 2002. PubMed ID: 12368912, referred to as 2436delG). In vitro functional studies by the same group confirmed the deleterious effect of this variant on splicing. This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs515726215; hg19: chr15-34532860;