rs150552508

Positions:

• chrX-100664899-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4 BP6_Very_Strong BP7 BS2

The NM_014467.3(SRPX2):​c.481C>A​(p.Arg161=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,209,407 control chromosomes in the GnomAD database, including 3 homozygotes. There are 635 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., 23 hem., cov: 23)
  • Exomes 𝑓: 0.0018 (3 hom. 612 hem.)
• Consequence: SRPX2 NM_014467.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.82

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.16).
• BP6: Variant X-100664899-C-A is Benign according to our data. Variant chrX-100664899-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 207371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100664899-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.83 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRPX2	NM_014467.3	c.481C>A	p.Arg161=	synonymous_variant	5/11	ENST00000373004.5	NP_055282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRPX2	ENST00000373004.5	c.481C>A	p.Arg161=	synonymous_variant	5/11	1	NM_014467.3	ENSP00000362095	P1

Frequencies

GnomAD3 genomes AF: 0.000989 AC: 111 AN: 112178 Hom.: 0 Cov.: 23 AF XY: 0.000669 AC XY: 23 AN XY: 34368

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000940

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00132

GnomAD3 exomes AF: 0.00102 AC: 184 AN: 179696 Hom.: 0 AF XY: 0.00111 AC XY: 72 AN XY: 64690

Gnomad AFR exome AF: 0.000156

Gnomad AMR exome AF: 0.0000735

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000194

Gnomad NFE exome AF: 0.00215

Gnomad OTH exome AF: 0.000903

GnomAD4 exome AF: 0.00181 AC: 1989 AN: 1097174 Hom.: 3 Cov.: 32 AF XY: 0.00169 AC XY: 612 AN XY: 362670

Gnomad4 AFR exome AF: 0.000189

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000396

Gnomad4 NFE exome AF: 0.00226

Gnomad4 OTH exome AF: 0.00143

GnomAD4 genome AF: 0.000989 AC: 111 AN: 112233 Hom.: 0 Cov.: 23 AF XY: 0.000668 AC XY: 23 AN XY: 34433

Gnomad4 AFR AF: 0.000129

Gnomad4 AMR AF: 0.0000939

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000163

Gnomad4 NFE AF: 0.00194

Gnomad4 OTH AF: 0.00130

Alfa AF: 0.000800 Hom.: 4

Bravo AF: 0.000880

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 22, 2015	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 04, 2018	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.16
CADD	Benign	11
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs150552508; hg19: chrX-99919896;