rs387906652

chr8-42417960-G-Achr8-42417960-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001257180.2(SLC20A2):c.1802C>T(p.Ser601Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,461,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S601W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SLC20A2 NM_001257180.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3 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 11 ACMG points.

• PM1: In a transmembrane_region Helical (size 15) in uniprot entity S20A2_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_001257180.2
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP2: Missense variant where missense usually causes diseases, SLC20A2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 8-42417960-G-A is Pathogenic according to our data. Variant chr8-42417960-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 29795.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-42417960-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC20A2	NM_001257180.2	c.1802C>T	p.Ser601Leu	missense_variant	11/11	ENST00000520262.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC20A2	ENST00000520262.6	c.1802C>T	p.Ser601Leu	missense_variant	11/11	2	NM_001257180.2	P1
SLC20A2	ENST00000342228.7	c.1802C>T	p.Ser601Leu	missense_variant	11/11	1		P1
SLC20A2	ENST00000520179.5	c.1802C>T	p.Ser601Leu	missense_variant	11/11	1		P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248332 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134646

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461046 Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12 AN XY: 726826

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic basal ganglia calcification 1 Pathogenic:3 Other:1

Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Aug 28, 2019	A heterozygous missense variant, NM_006749.4(SLC20A2):c.1802C>T, has been identified in exon 11 of 11 of the SLC20A2 gene. The variant is predicted to result in a major amino acid change from a serine to a leucine at position 601 of the protein, NP_006740.1(SLC20A2):p.(Ser601Leu). The serine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the helical transmembrane XI functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.0004% (1 heterozygote, 0 homozygotes). The variant has previously been described as pathogenic and segregated with disease in a family with familial idiopathic basal ganglia calcification (ClinVar, Wang, C., et al. (2012), Hsu, S., et al. (2013)). Functional analysis in transfected Xenopus oocyte cells demonstrated impaired phosphate uptake activity (Wang, C., et al. (2012)). A different variant in the same codon resulting in a change to a tryptophan, p.(Ser601Trp) has also been reported as pathogenic (ClinVar, Wang, C., et al. (2012)). In addition, functional studies for this variant in both human and Xenopus cell lines showed a similar impairment in phosphate transport (Wang, C., et al. (2012), Guo, X., et al. (2019)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.3	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.95
MutPred		0.75		Loss of glycosylation at S601 (P = 0.0637);Loss of glycosylation at S601 (P = 0.0637);Loss of glycosylation at S601 (P = 0.0637);
MVP		0.87
MPC		1.5
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.76
gMVP		0.99

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; COSMIC: COSV60603043;