rs398122396

Positions:

• chr8-42417930-CGGGA-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_001257180.2(SLC20A2):​c.1828_1831delTCCC​(p.Ser610fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,612 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC20A2 NM_001257180.2 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0669 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-42417930-CGGGA-C is Pathogenic according to our data. Variant chr8-42417930-CGGGA-C is described in ClinVar as [Pathogenic]. Clinvar id is 75231.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC20A2	NM_001257180.2	c.1828_1831delTCCC	p.Ser610fs	frameshift_variant	11/11	ENST00000520262.6	NP_001244109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC20A2	ENST00000520262.6	c.1828_1831delTCCC	p.Ser610fs	frameshift_variant	11/11	2	NM_001257180.2	ENSP00000429754.1
SLC20A2	ENST00000342228.7	c.1828_1831delTCCC	p.Ser610fs	frameshift_variant	11/11	1		ENSP00000340465.3
SLC20A2	ENST00000520179.5	c.1828_1831delTCCC	p.Ser610fs	frameshift_variant	11/11	1		ENSP00000429712.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461612 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

SLC20A2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 31, 2024

The SLC20A2 c.1828_1831delTCCC variant is predicted to result in a frameshift and premature protein termination (p.Ser610Alafs*18). This variant occurs within the terminal exon of SLC20A2 and has been reported in nine members of a family presenting with idiopathic basal ganglia calcification (Family F2 in Hsu et al. 2013. PubMed ID: 23334463). Of note, an additional member of family F2 in Hsu et al. was reported as affected but did not have the variant. This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in SLC20A2 are expected to be pathogenic and another truncating variant has been documented downstream of p.Ser610 (Hozumi et al. 2018. PubMed ID: 29627011). Based on this evidence, this variant is interpreted as pathogenic. -

Idiopathic basal ganglia calcification 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2013

- -

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: rs398122396; hg19: chr8-42275448;