chr15-34243983-T-TA

Variant names:

• chr15-34243983-T-TA
• rs515726217
• NM_001365088.1:c.2032dupT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001365088.1(SLC12A6):​c.2032dupT​(p.Tyr678LeufsTer41) 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Y678Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC12A6 NM_001365088.1 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.30
• Publications: 2 publications found

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]

SLC12A6 Gene-Disease associations (from GenCC):

• agenesis of the corpus callosum with peripheral neuropathy

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Charcot-Marie-Tooth disease, axonal, IIa 2II

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

LOC124903461 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 15-34243983-T-TA is Pathogenic according to our data. Variant chr15-34243983-T-TA is described in CliVar as Pathogenic. Clinvar id is 136176.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-34243983-T-TA is described in CliVar as Pathogenic. Clinvar id is 136176.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-34243983-T-TA is described in CliVar as Pathogenic. Clinvar id is 136176.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-34243983-T-TA is described in CliVar as Pathogenic. Clinvar id is 136176.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-34243983-T-TA is described in CliVar as Pathogenic. Clinvar id is 136176.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-34243983-T-TA is described in CliVar as Pathogenic. Clinvar id is 136176.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-34243983-T-TA is described in CliVar as Pathogenic. Clinvar id is 136176.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-34243983-T-TA is described in CliVar as Pathogenic. Clinvar id is 136176.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-34243983-T-TA is described in CliVar as Pathogenic. Clinvar id is 136176.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-34243983-T-TA is described in CliVar as Pathogenic. Clinvar id is 136176.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-34243983-T-TA is described in CliVar as Pathogenic. Clinvar id is 136176.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-34243983-T-TA is described in CliVar as Pathogenic. Clinvar id is 136176.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-34243983-T-TA is described in CliVar as Pathogenic. Clinvar id is 136176.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-34243983-T-TA is described in CliVar as Pathogenic. Clinvar id is 136176.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-34243983-T-TA is described in CliVar as Pathogenic. Clinvar id is 136176.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-34243983-T-TA is described in CliVar as Pathogenic. Clinvar id is 136176.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-34243983-T-TA is described in CliVar as Pathogenic. Clinvar id is 136176.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A6	NM_001365088.1	c.2032dupT	p.Tyr678LeufsTer41	frameshift_variant	Exon 16 of 26	ENST00000354181.8	NP_001352017.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A6	ENST00000354181.8	c.2032dupT	p.Tyr678LeufsTer41	frameshift_variant	Exon 16 of 26	1	NM_001365088.1	ENSP00000346112.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Apr 11, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs515726217; hg19: chr15-34536184;