rs515726218

Variant names:

• chr15-34250905-CAGAGGGAA-C
• rs515726218
• NM_001365088.1:c.1478_1485delTTCCCTCT

Variant summary

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

The NM_001365088.1(SLC12A6):​c.1478_1485delTTCCCTCT​(p.Phe493CysfsTer48) 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). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SLC12A6 NM_001365088.1 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 10.0
• Publications: 3 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: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, G2P
• Charcot-Marie-Tooth disease, axonal, IIa 2II

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

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 15-34250905-CAGAGGGAA-C is Pathogenic according to our data. Variant chr15-34250905-CAGAGGGAA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 136177.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365088.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A6	NM_001365088.1	MANE Select	c.1478_1485delTTCCCTCT	p.Phe493CysfsTer48	frameshift	Exon 11 of 26	NP_001352017.1	Q9UHW9-1
	SLC12A6	NM_133647.2		c.1478_1485delTTCCCTCT	p.Phe493CysfsTer48	frameshift	Exon 10 of 25	NP_598408.1	Q9UHW9-1
	SLC12A6	NM_001042496.2		c.1451_1458delTTCCCTCT	p.Phe484CysfsTer48	frameshift	Exon 11 of 26	NP_001035961.1	Q9UHW9-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A6	ENST00000354181.8	TSL:1 MANE Select	c.1478_1485delTTCCCTCT	p.Phe493CysfsTer48	frameshift	Exon 11 of 26	ENSP00000346112.3	Q9UHW9-1
	SLC12A6	ENST00000560611.5	TSL:1	c.1478_1485delTTCCCTCT	p.Phe493CysfsTer48	frameshift	Exon 10 of 25	ENSP00000454168.1	Q9UHW9-1
	SLC12A6	ENST00000558589.5	TSL:1	c.1451_1458delTTCCCTCT	p.Phe484CysfsTer48	frameshift	Exon 11 of 26	ENSP00000452776.1	Q9UHW9-4

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Agenesis of the corpus callosum with peripheral neuropathy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs515726218;

hg19: chr15-34543106;