rs886040968

Variant names:

• chr5-128178663-ATGTCTGGTGGC-A
• rs886040968
• NM_001046.3:c.3076_3086delGTCTGGTGGCT

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_001046.3(SLC12A2):​c.3076_3086delGTCTGGTGGCT​(p.Val1026PhefsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC12A2 NM_001046.3 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.92
• Publications: 4 publications found

Genes affected

SLC12A2 (HGNC:10911): (solute carrier family 12 member 2) The protein encoded by this gene mediates sodium and chloride transport and reabsorption. The encoded protein is a membrane protein and is important in maintaining proper ionic balance and cell volume. This protein is phosphorylated in response to DNA damage. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

SLC12A2 Gene-Disease associations (from GenCC):

• Delpire-McNeill syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal dominant 78

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

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-128178663-ATGTCTGGTGGC-A is Pathogenic according to our data. Variant chr5-128178663-ATGTCTGGTGGC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 267304.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A2	NM_001046.3	c.3076_3086delGTCTGGTGGCT	p.Val1026PhefsTer2	frameshift_variant	Exon 22 of 27	ENST00000262461.7	NP_001037.1
SLC12A2	NM_001256461.2	c.3028_3038delGTCTGGTGGCT	p.Val1010PhefsTer2	frameshift_variant	Exon 21 of 26		NP_001243390.1
SLC12A2	NR_046207.2	n.3265_3275delGTCTGGTGGCT		non_coding_transcript_exon_variant	Exon 22 of 27
SLC12A2	XM_047417591.1	c.*120_*130delTGTCTGGTGGC		downstream_gene_variant			XP_047273547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A2	ENST00000262461.7	c.3076_3086delGTCTGGTGGCT	p.Val1026PhefsTer2	frameshift_variant	Exon 22 of 27	1	NM_001046.3	ENSP00000262461.2

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Infant onset multiple organ failure Pathogenic:1

Oct 01, 2016

Undiagnosed Diseases Program Translational Research Laboratory, National Institutes of Health

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs886040968; hg19: chr5-127514355;