8-42417829-T-C

Variant names:

• chr8-42417829-T-C
• NM_001257180.2:c.1933A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001257180.2(SLC20A2):​c.1933A>G​(p.Met645Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M645K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC20A2 NM_001257180.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.990

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12841296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC20A2	NM_001257180.2	c.1933A>G	p.Met645Val	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.1933A>G	p.Met645Val	missense_variant	Exon 11 of 11	2	NM_001257180.2	ENSP00000429754.1
SLC20A2	ENST00000342228.7	c.1933A>G	p.Met645Val	missense_variant	Exon 11 of 11	1		ENSP00000340465.3
SLC20A2	ENST00000520179.5	c.1933A>G	p.Met645Val	missense_variant	Exon 11 of 11	1		ENSP00000429712.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461854 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33476

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39698

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53412

Gnomad4 NFE exome AF: 0.00000360 AC: 4 AN: 1111990

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic basal ganglia calcification 1 Uncertain:1

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with idiopathic basal ganglia calcification (MIM#1213600). Missense variants have demonstrated a dominant negative effect on protein function (PMID: 27943094), while both missense variants and variants resulting in a premature termination codon have been reported with a loss of function effect (PMID: 24209445, OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (123 heterozygotes, 3 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0709 - Another missense variant comparable to the one identified in this case has low previous evidence for being benign. This alternative missense variant (p.Met645Lys) has been reported as benign (ClinVar). (SB) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 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	Benign	0.062
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	8.4
DANN	Benign	0.52
DEOGEN2	Benign	0.082	T;T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.67	.;.;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.14	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.79	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.60	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.10
MutPred		0.42		Gain of catalytic residue at M645 (P = 0.0254);Gain of catalytic residue at M645 (P = 0.0254);Gain of catalytic residue at M645 (P = 0.0254);
MVP		0.31
MPC		0.64
ClinPred		0.098	T
GERP RS		1.1
Varity_R		0.052
gMVP		0.80
Mutation Taster		=89/11	polymorphism

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-42275347; COSMIC: COSV60602688;