8-42428829-C-T

Position:

• chr8-42428829-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 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. 12/21 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

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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SLC20A2. . Gene score misZ 2.6315 (greater than the threshold 3.09). Trascript score misZ 3.281 (greater than threshold 3.09). GenCC has associacion of gene with basal ganglia calcification, idiopathic, 1, bilateral striopallidodentate calcinosis.
• 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 [Likely_pathogenic]. Clinvar id is 29796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42428829-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC20A2	NM_001257180.2	c.1723G>A	p.Glu575Lys	missense_variant	10/11	ENST00000520262.6	NP_001244109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC20A2	ENST00000520262.6	c.1723G>A	p.Glu575Lys	missense_variant	10/11	2	NM_001257180.2	ENSP00000429754.1
SLC20A2	ENST00000342228.7	c.1723G>A	p.Glu575Lys	missense_variant	10/11	1		ENSP00000340465.3
SLC20A2	ENST00000520179.5	c.1723G>A	p.Glu575Lys	missense_variant	10/11	1		ENSP00000429712.1

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

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: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Idiopathic basal ganglia calcification 1 Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jul 13, 2021	PS3, PP2, PS4_Supporting, PM2 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 12, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Nov 21, 2017	- -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with basal ganglia calcification, idiopathic, 1 (MIM#213600). Missense variants can have both loss of function and dominant negative effects, while protein truncating variants are only known to have loss of function effects (PMID: 24209445, 23437308, 22327515, 27943094). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. In two large pedigrees, mutation positive family members are all seen to have basal ganglia calcification but only some were symptomatic (PMID: 22327515). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated phosphate transporter family domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by two clinical laboratories in ClinVar and observed in two individuals and one family with basal ganglia calcification in the literature (Schottlaender, 2013; PMID: 22327515, 30609140). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to significantly impair the transport of inorganic phosphate (PMID: 22327515). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

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;D;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;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.5	M;M;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.99
MutPred		0.78		Gain of ubiquitination at E575 (P = 0.0198);Gain of ubiquitination at E575 (P = 0.0198);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

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