NM_001257180.2:c.1802C>T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 11P and 4B. PM1 PM5 PP2 PP3_Strong PP5_Moderate BS2

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. 12/21 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 Likely 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 Likely_pathogenic. Variant got 7 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-42417960-G-C 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, 0.957
• 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].
• BS2: High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC20A2	NM_001257180.2	c.1802C>T	p.Ser601Leu	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>T	p.Ser601Leu	missense_variant	Exon 11 of 11	2	NM_001257180.2	ENSP00000429754.1
SLC20A2	ENST00000342228.7	c.1802C>T	p.Ser601Leu	missense_variant	Exon 11 of 11	1		ENSP00000340465.3
SLC20A2	ENST00000520179.5	c.1802C>T	p.Ser601Leu	missense_variant	Exon 11 of 11	1		ENSP00000429712.1

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

Feb 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 28, 2019

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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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	0.51	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
LIST_S2	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
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;