8-42417960-G-C

Variant names:

• chr8-42417960-G-C
• rs387906652
• NM_001257180.2:c.1802C>G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_001257180.2(SLC20A2):​c.1802C>G​(p.Ser601Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S601L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SLC20A2 NM_001257180.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• 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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a transmembrane_region Helical (size 15) in uniprot entity S20A2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001257180.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-42417960-G-A is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in the SLC20A2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 2.6315 (below the threshold of 3.09). Trascript score misZ: 3.281 (above the threshold of 3.09). GenCC associations: The gene is linked to basal ganglia calcification, idiopathic, 1, bilateral striopallidodentate calcinosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 8-42417960-G-C is Pathogenic according to our data. Variant chr8-42417960-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 29794.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-42417960-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC20A2	NM_001257180.2	c.1802C>G	p.Ser601Trp	missense_variant	Exon 11 of 11	ENST00000520262.6	NP_001244109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC20A2	ENST00000520262.6	c.1802C>G	p.Ser601Trp	missense_variant	Exon 11 of 11	2	NM_001257180.2	ENSP00000429754.1
SLC20A2	ENST00000342228.7	c.1802C>G	p.Ser601Trp	missense_variant	Exon 11 of 11	1		ENSP00000340465.3
SLC20A2	ENST00000520179.5	c.1802C>G	p.Ser601Trp	missense_variant	Exon 11 of 11	1		ENSP00000429712.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Idiopathic basal ganglia calcification 1 Pathogenic:1 Other:1

Feb 12, 2012

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
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M;M;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.90
MutPred		0.78		Gain of MoRF binding (P = 0.0385);Gain of MoRF binding (P = 0.0385);Gain of MoRF binding (P = 0.0385);
MVP		0.94
MPC		1.9
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.87
gMVP		1.0

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: rs387906652; hg19: chr8-42275478;