rs398122397

Variant names:

• chr8-42459924-GAC-G
• rs398122397
• NM_001257180.2:c.583_584delGT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001257180.2(SLC20A2):​c.583_584delGT​(p.Val195LeufsTer62) variant causes a frameshift change. 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. V195V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC20A2 NM_001257180.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.13
• Publications: 1 publications found

Genes affected

SLC20A2 (HGNC:10947): (solute carrier family 20 member 2) This gene encodes a member of the inorganic phosphate transporter family. The encoded protein is a type 3 sodium-dependent phosphate symporter that plays an important role in phosphate homeostasis by mediating cellular phosphate uptake. The encoded protein also confers susceptibility to viral infection as a gamma-retroviral receptor. Mutations in this gene may play a role in familial idiopathic basal ganglia calcification. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

SLC20A2 Gene-Disease associations (from GenCC):

• basal ganglia calcification, idiopathic, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp
• bilateral striopallidodentate calcinosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 8-42459924-GAC-G is Pathogenic according to our data. Variant chr8-42459924-GAC-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 75233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001257180.2. 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
	SLC20A2	NM_001257180.2	MANE Select	c.583_584delGT	p.Val195LeufsTer62	frameshift	Exon 5 of 11	NP_001244109.1	A0A384MR38
	SLC20A2	NM_001257181.2		c.583_584delGT	p.Val195LeufsTer62	frameshift	Exon 5 of 11	NP_001244110.1	Q08357
	SLC20A2	NM_006749.5		c.583_584delGT	p.Val195LeufsTer62	frameshift	Exon 5 of 11	NP_006740.1	Q08357

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC20A2	ENST00000520262.6	TSL:2 MANE Select	c.583_584delGT	p.Val195LeufsTer62	frameshift	Exon 5 of 11	ENSP00000429754.1	Q08357
	SLC20A2	ENST00000342228.7	TSL:1	c.583_584delGT	p.Val195LeufsTer62	frameshift	Exon 5 of 11	ENSP00000340465.3	Q08357
	SLC20A2	ENST00000520179.5	TSL:1	c.583_584delGT	p.Val195LeufsTer62	frameshift	Exon 5 of 11	ENSP00000429712.1	Q08357

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Idiopathic basal ganglia calcification 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.1
Mutation Taster		=1/199	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

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

Other links and lift over

dbSNP: rs398122397;

hg19: chr8-42317442;