rs1555380716

Positions:

• chr15-34255385-G-GC

Variant summary

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

The NM_001365088.1(SLC12A6):​c.752_753insG​(p.Ser252LeufsTer38) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G251G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC12A6 NM_001365088.1 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.91

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]

(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 15-34255385-G-GC is Pathogenic according to our data. Variant chr15-34255385-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A6	NM_001365088.1	c.752_753insG	p.Ser252LeufsTer38	frameshift_variant	8/26	ENST00000354181.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A6	ENST00000354181.8	c.752_753insG	p.Ser252LeufsTer38	frameshift_variant	8/26	1	NM_001365088.1	A1
	ENST00000559867.1	n.105dup		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertelorism;C0175754:Corpus callosum, agenesis of;C0239234:Low-set ears;C0424503:Abnormal facial shape;C1850049:Clinodactyly of the 5th finger Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 05, 2021

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with SLC12A6-related conditions. ClinVar contains an entry for this variant (Variation ID: 523557). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser252Leufs*38) 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). -

Computational scores

Source: dbNSFP v4.3

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: rs1555380716; hg19: chr15-34547586;