rs121918363

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014467.3(SRPX2):c.980A>G(p.Asn327Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000871 in 1,209,994 control chromosomes in the GnomAD database, including 2 homozygotes. There are 334 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).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., 12 hem., cov: 24)

Exomes 𝑓: 0.00092 ( 2 hom. 322 hem. )

Consequence

SRPX2
NM_014467.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6

Conservation

PhyloP100: 1.70

Variant links:

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]

SRPX2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04739812).

BS2

High Hemizygotes in GnomAd4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRPX2	NM_014467.3 link	c.980A>G	p.Asn327Ser	missense_variant	Exon 9 of 11	ENST00000373004.5	NP_055282.1	O60687

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRPX2	ENST00000373004.5 link	c.980A>G	p.Asn327Ser	missense_variant	Exon 9 of 11	1	NM_014467.3	ENSP00000362095.3		O60687

Frequencies

GnomAD3 genomes

AF:

0.000402

AC:

AN:

111823

Hom.:

Cov.:

AF XY:

0.000353

AC XY:

AN XY:

33993

show subpopulations

Gnomad AFR

AF:

0.000130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000946

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:

0.000752

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000572

AC:

105

AN:

183471

Hom.:

AF XY:

0.000383

AC XY:

AN XY:

67905

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000125

Gnomad NFE exome

AF:

0.00121

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000919

AC:

1009

AN:

1098171

Hom.:

Cov.:

AF XY:

0.000886

AC XY:

322

AN XY:

363529

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

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:

0.000370

Gnomad4 NFE exome

AF:

0.00116

Gnomad4 OTH exome

AF:

0.000369

GnomAD4 genome

AF:

0.000402

AC:

AN:

111823

Hom.:

Cov.:

AF XY:

0.000353

AC XY:

AN XY:

33993

show subpopulations

Gnomad4 AFR

AF:

0.000130

Gnomad4 AMR

AF:

0.0000946

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000752

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000769

Hom.:

Bravo

AF:

0.000374

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00138

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000469

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Nov 19, 2013

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SRPX2 p.N327S variant was identified in 2 of 348 proband chromosomes (frequency: 0.0057) from individuals or families with Rolandic epilepsy (RE) and atypical RE and was present in 1 of 806 control chromosomes (frequency: 0.0012) from healthy individuals (Reinthaler_2014_PMID:24995671). Reinthaler et al. (2014) suggested the p.N327S variant does not play a major role in RE. The p.N327S variant was identified in a three generation family with atypical RE, verbal dyspraxia and cognitive impairment of variable degrees (Roll_2006_PMID:16497722). However a potentially deleterious variant, p.A716T, in the GRIN2A gene was found in a subsequent study of this family that segregated in all affected individuals (Lesca_2013_PMID:23933820). All but 2 affected family members with the SRPX2 mutation also carried the GRIN2A mutation, and all patients with the GRIN2A mutation had seizures, whereas the 2 patients with only the SRPX2 mutation and not the GRIN2A mutation did not have seizures (Lesca_2013_PMID:23933820). In another study, the p.N327S variant was identified in a boy with language and intellectual difficulties (Chen_2017_PMID:28440294). The variant was identified in dbSNP (ID: rs121918363), LOVD 3.0 (classified as likely benign) and in ClinVar (classified as benign by Invitae, likely benign by Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen and as uncertain significance by EGL Genetics, Swiss Institute of Bioinformatics, GeneDx and Genetic Services Laboratory, University of Chicago). The variant was identified in control databases in 111 of 205296 chromosomes (1 homozygous; 27 hemizygous) at a frequency of 0.000541 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 104 of 92730 chromosomes (freq: 0.001122), Other in 1 of 5338 chromosomes (freq: 0.000187), African in 3 of 18978 chromosomes (freq: 0.000158), European (Finnish) in 2 of 18621 chromosomes (freq: 0.000107) and Latino in 1 of 28049 chromosomes (freq: 0.000036), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The variant occurs outside of the splicing consensus sequence and two of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity.The p.Asn327 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. Using an in utero Srpx2 silencing approach in mouse models, the expression of the mutant p.N327S-SRPX2 protein was found to lead to impaired development of the cerebral cortex and post-natal epileptiform activity (Salmi_2013_PMID:23831613). The p.N327S mutation was also shown to lead to gain-of-glycosylation of the mutant SRPX2 protein which causes partial retentionof the altered protein within the endoplasmic reticulumin a transfected-cell model (Roll_2006_PMID:16497722). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Jul 11, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asn327Ser (AAC>AGC): c.980 A>G in exon 9 in the SRPX2 gene (NM_014467.2).The N327S variant in the SRPX2 gene has been reported previously in association with Rolandic seizures and intellectual disability (Roll et al., 2006). The N327S variant segregated with the phenotype in multiple family members and results in a gain-of-function glycosylation that likely disrupts protein folding and function. However, Piton et al. later questioned the pathogenicity of the N327S variant because of the frequency in control populations (2013). The NHLBI ESP Exome Sequencing Project reports N327S was observed in 0.16% (11/6728) alleles from individuals of European background, including 3 hemizygous males. The N327S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret N327S as a variant of unknown significance, which may be related to the reported brain malformation. The variant is found in ,SRPX2 panel(s). -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Rolandic epilepsy, intellectual disability, and speech dyspraxia, X-linked

Uncertain:2Benign:2

Jul 02, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Rolandic epilepsy, mental retardation, and speech dyspraxia, X-linked, in X-linked Recessive manner. The following ACMG Tag(s) were applied: BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age (PMID:24995671) (PMID:23871722). PS3-Supporting => PS3 downgraded in strength to Supporting (PMID:16497722). -

Aug 01, 2014

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified

Benign:1

Dec 29, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.82

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.063

T;.

FATHMM_MKL

Benign

0.53

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.047

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.39

N;.

REVEL

Benign

0.080

Sift

Benign

0.036

D;.

Sift4G

Benign

0.14

T;.

Polyphen

0.063

B;.

Vest4

0.69

MVP

0.43

MPC

0.13

ClinPred

0.047

GERP RS

5.5

Varity_R

0.11

gMVP

0.21

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over