rs121908428

Positions:

• chr15-34243993-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000354181.8(SLC12A6):​c.2023C>T​(p.Arg675Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000277 in 1,442,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R675R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SLC12A6 ENST00000354181.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 4.08

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]

LOC124903461 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-34243993-G-A is Pathogenic according to our data. Variant chr15-34243993-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-34243993-G-A is described in Lovd as [Pathogenic]. Variant chr15-34243993-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A6	NM_001365088.1	c.2023C>T	p.Arg675Ter	stop_gained	16/26	ENST00000354181.8	NP_001352017.1
LOC124903461	XR_007064576.1	n.816+52G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A6	ENST00000354181.8	c.2023C>T	p.Arg675Ter	stop_gained	16/26	1	NM_001365088.1	ENSP00000346112	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1442752 Hom.: 0 Cov.: 27 AF XY: 0.00000278 AC XY: 2 AN XY: 719246

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: 0.00000365

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Agenesis of the corpus callosum with peripheral neuropathy Pathogenic:4 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2002	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2017	Variant summary: The SLC12A6 c.2023C>T (p.Arg675X) variant results in a premature termination codon, predicted to cause a truncated or absent SLC12A6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 121074 control chromosomes. A publication cites the variant in two homozygous siblings affected witn Andermann Syndrome. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 5327). This premature translational stop signal has been observed in individual(s) with agenesis of the corpus callosum with peripheral neuropathy (PMID: 12368912). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg675*) 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). -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

SLC12A6-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 22, 2024

The SLC12A6 c.2023C>T variant is predicted to result in premature protein termination (p.Arg675*). This variant was reported in the homozygous state in an individual with peripheral neuropathy associated with agenesis of the corpus callosum (ACCPN) and also in the heterozygous state in an unaffected sibling, indicating an autosomal recessive inheritance pattern (Howard et al. 2002. PubMed ID: 12368912). This variant has not been reported in gnomAD, indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/5327/). Nonsense variants in SLC12A6 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
Vest4		0.86
GERP RS		3.9

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: rs121908428; hg19: chr15-34536194; COSMIC: COSV99273634; COSMIC: COSV99273634;