rs758845090

chrX-100665356-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_014467.3(SRPX2):c.646G>A(p.Gly216Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,208,544 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G216G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: SRPX2 NM_014467.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.65

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29234874).
• BP6: Variant X-100665356-G-A is Benign according to our data. Variant chrX-100665356-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284208.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRPX2	NM_014467.3	c.646G>A	p.Gly216Ser	missense_variant	6/11	ENST00000373004.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRPX2	ENST00000373004.5	c.646G>A	p.Gly216Ser	missense_variant	6/11	1	NM_014467.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000891 AC: 1 AN: 112250 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34428

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000936

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000283 AC: 5 AN: 176767 Hom.: 0 AF XY: 0.0000324 AC XY: 2 AN XY: 61709

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000185

Gnomad ASJ exome AF: 0.00

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: 0.00000456 AC: 5 AN: 1096294 Hom.: 0 Cov.: 32 AF XY: 0.00000553 AC XY: 2 AN XY: 361794

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000891 AC: 1 AN: 112250 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34428

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000936

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SRPX2-related disease. ClinVar contains an entry for this variant (Variation ID: 284208). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces glycine with serine at codon 216 of the SRPX2 protein (p.Gly216Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.23
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.050	T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.4	N;.;.
REVEL	Benign	0.19
Sift	Uncertain	0.028	D;.;.
Sift4G	Uncertain	0.021	D;.;.
Polyphen		0.95	P;.;.
Vest4		0.63
MutPred		0.65		Gain of glycosylation at G216 (P = 0.047);Gain of glycosylation at G216 (P = 0.047);.;
MVP		0.57
MPC		0.67
ClinPred		0.32	T
GERP RS		5.6
Varity_R		0.58
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs758845090; hg19: chrX-99920353;