8-42428829-C-T

Variant names:

• chr8-42428829-C-T
• rs387906653
• NM_001257180.2:c.1723G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001257180.2(SLC20A2):​c.1723G>A​(p.Glu575Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC20A2 NM_001257180.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.91
• Publications: 9 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: Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• bilateral striopallidodentate calcinosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a mutagenesis_site Abolishes phosphate but not sodium uptake; when associated with Q-55 and Q-91. (size 0) in uniprot entity S20A2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 8-42428829-C-T is Pathogenic according to our data. Variant chr8-42428829-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 29796.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.1723G>A	p.Glu575Lys	missense	Exon 10 of 11	NP_001244109.1	A0A384MR38
	SLC20A2	NM_001257181.2		c.1723G>A	p.Glu575Lys	missense	Exon 10 of 11	NP_001244110.1	Q08357
	SLC20A2	NM_006749.5		c.1723G>A	p.Glu575Lys	missense	Exon 10 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.1723G>A	p.Glu575Lys	missense	Exon 10 of 11	ENSP00000429754.1	Q08357
	SLC20A2	ENST00000342228.7	TSL:1	c.1723G>A	p.Glu575Lys	missense	Exon 10 of 11	ENSP00000340465.3	Q08357
	SLC20A2	ENST00000520179.5	TSL:1	c.1723G>A	p.Glu575Lys	missense	Exon 10 of 11	ENSP00000429712.1	Q08357

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448922 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720416

African (AFR) AF: 0.00 AC: 0 AN: 32720

American (AMR) AF: 0.00 AC: 0 AN: 43024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25348

East Asian (EAS) AF: 0.00 AC: 0 AN: 38690

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106108

Other (OTH) AF: 0.00 AC: 0 AN: 59874

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Idiopathic basal ganglia calcification 1 (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.78		Gain of ubiquitination at E575 (P = 0.0198)
MVP		0.85
MPC		1.7
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.73
gMVP		0.98
Mutation Taster		=0/100	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

Other links and lift over

dbSNP: rs387906653; hg19: chr8-42286347; COSMIC: COSV60601673;