X-100646371-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014467.3(SRPX2):c.49C>G(p.Leu17Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: SRPX2 NM_014467.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45

Genes affected

SRPX2 (HGNC:30668): (sushi repeat containing protein X-linked 2) This gene encodes a secreted protein that contains three sushi repeat motifs. The encoded protein may play a role in the development of speech and language centers in the brain. This protein may also be involved in angiogenesis. Mutations in this gene are the cause of bilateral perisylvian polymicrogyria, rolandic epilepsy, speech dyspraxia and cognitive disability. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22465748).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRPX2	NM_014467.3	c.49C>G	p.Leu17Val	missense_variant	2/11	ENST00000373004.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRPX2	ENST00000373004.5	c.49C>G	p.Leu17Val	missense_variant	2/11	1	NM_014467.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rolandic epilepsy, intellectual disability, and speech dyspraxia, X-linked Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Aug 28, 2019

A heterozygous missense variant was identified, NM_014467.2(SRPX2):c.49C>G in exon 2 of 11 of the SPRX2 gene. This substitution is predicted to create a minor amino acid change from leucine to valine at position 17 of the protein, NP_055282.1(SPRX2):p.(Leu17Val). The leucine at this position has high conservation (100 vertebrates, UCSC), but is not situated in a known functional domain. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is not present in the gnomAD population database. The variant has not been previously reported in a clinical testing setting. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	14
Dann	Benign	0.96
DEOGEN2	Benign	0.063	T;.;.
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L;.;.
MutationTaster	Benign	0.71	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.16	N;.;.
REVEL	Benign	0.15
Sift	Benign	0.48	T;.;.
Sift4G	Benign	0.40	T;.;.
Polyphen		0.96	P;.;.
Vest4		0.35
MutPred		0.68		Gain of catalytic residue at L17 (P = 0.0954);Gain of catalytic residue at L17 (P = 0.0954);Gain of catalytic residue at L17 (P = 0.0954);
MVP		0.38
MPC		0.16
ClinPred		0.35	T
GERP RS		4.2
Varity_R		0.065
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1422524189; hg19: chrX-99901368;