chrX-100667342-C-A

Position:

chrX-100667342-C-A

Variant summary

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

The NM_014467.3(SRPX2):c.1030C>A(p.Leu344Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000259 in 1,209,692 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 91 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 0.0013 ( 0 hom., 40 hem., cov: 24)

Exomes 𝑓: 0.00015 ( 0 hom. 51 hem. )

Consequence

SRPX2
NM_014467.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:4

Conservation

PhyloP100: 5.66

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=0.01242426).

BS2

High Hemizygotes in GnomAd4 at 40 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRPX2	NM_014467.3 linkuse as main transcript	c.1030C>A	p.Leu344Ile	missense_variant	9/11	ENST00000373004.5	NP_055282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRPX2	ENST00000373004.5 linkuse as main transcript	c.1030C>A	p.Leu344Ile	missense_variant	9/11	1	NM_014467.3	ENSP00000362095	P1

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

145

AN:

111925

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

34093

show subpopulations

Gnomad AFR

AF:

0.00424

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

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:

0.0000939

Gnomad OTH

AF:

0.000661

GnomAD3 exomes

AF:

0.000343

AC:

AN:

183472

Hom.:

AF XY:

0.000265

AC XY:

AN XY:

67914

show subpopulations

Gnomad AFR exome

AF:

0.00395

Gnomad AMR exome

AF:

0.000219

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:

0.0000488

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000153

AC:

168

AN:

1097714

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

AN XY:

363074

show subpopulations

Gnomad4 AFR exome

AF:

0.00394

Gnomad4 AMR exome

AF:

0.000227

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:

0.0000380

Gnomad4 OTH exome

AF:

0.000326

GnomAD4 genome

AF:

0.00129

AC:

145

AN:

111978

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

34156

show subpopulations

Gnomad4 AFR

AF:

0.00423

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000939

Gnomad4 OTH

AF:

0.000652

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.00146

ESP6500AA

AF:

0.00495

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000354

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Pathogenic:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2014	p.Leu344Ile (CTC>ATC): c.1030 C>A in exon 9 in the SRPX2 gene (NM_014467.2). The L344I variant in the SRPX2 gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The L344I variant has been identified at low frequency in African Americans (0.49%, 19/3835 alleles) by the NHLBI Exome Sequencing Project and was not observed in the homozygous state in any individual within this population. The L344I 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 across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret L344I as a variant of unknown significance. The variant is found in CHILD-EPI,EPILEPSY panel(s). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 08, 2018

- -

SRPX2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.062

T;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

2.0

M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.89

N;.

REVEL

Benign

0.19

Sift

Uncertain

0.010

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.61

MVP

0.38

MPC

0.70

ClinPred

0.021

GERP RS

5.3

Varity_R

0.66

gMVP

0.45

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