rs146051561

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_014467.3(SRPX2):c.1373G>A(p.Arg458Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,208,481 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 78 hemizygotes in GnomAD. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., 31 hem., cov: 22)

Exomes 𝑓: 0.00015 ( 0 hom. 47 hem. )

Consequence

SRPX2
NM_014467.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.893

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043203235).

BP6

Variant X-100670962-G-A is Benign according to our data. Variant chrX-100670962-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 130374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd at 31 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRPX2	NM_014467.3 linkuse as main transcript	c.1373G>A	p.Arg458Gln	missense_variant	11/11	ENST00000373004.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SRPX2	ENST00000373004.5 linkuse as main transcript	c.1373G>A	p.Arg458Gln	missense_variant	11/11	1	NM_014467.3	P1
SRPX2	ENST00000640282.1 linkuse as main transcript	c.*108G>A		3_prime_UTR_variant	3/3	5
SRPX2	ENST00000638920.1 linkuse as main transcript	n.1376G>A		non_coding_transcript_exon_variant	10/10	5

Frequencies

GnomAD3 genomes

AF:

0.00121

AC:

135

AN:

111813

Hom.:

Cov.:

AF XY:

0.000912

AC XY:

AN XY:

33997

show subpopulations

Gnomad AFR

AF:

0.00403

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000659

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:

0.00269

GnomAD3 exomes

AF:

0.000340

AC:

AN:

179344

Hom.:

AF XY:

0.000188

AC XY:

AN XY:

63992

show subpopulations

Gnomad AFR exome

AF:

0.00325

Gnomad AMR exome

AF:

0.000554

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:

0.0000376

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.000150

AC:

164

AN:

1096615

Hom.:

Cov.:

AF XY:

0.000130

AC XY:

AN XY:

362021

show subpopulations

Gnomad4 AFR exome

AF:

0.00390

Gnomad4 AMR exome

AF:

0.000485

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:

0.0000238

Gnomad4 OTH exome

AF:

0.000434

GnomAD4 genome

AF:

0.00122

AC:

136

AN:

111866

Hom.:

Cov.:

AF XY:

0.000910

AC XY:

AN XY:

34060

show subpopulations

Gnomad4 AFR

AF:

0.00406

Gnomad4 AMR

AF:

0.000658

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:

0.00266

Alfa

AF:

0.000195

Hom.:

Bravo

AF:

0.00134

ESP6500AA

AF:

0.00495

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000379

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 08, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 21, 2017	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 05, 2019

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2022

- -

SRPX2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 07, 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

0.067

BayesDel_addAF

Benign

-0.89

BayesDel_noAF

Benign

-1.1

Cadd

Benign

2.3

Dann

Benign

0.88

DEOGEN2

Benign

0.041

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.57

M_CAP

Benign

0.0067

MetaRNN

Benign

0.0043

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

MutationTaster

Benign

1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

0.29

REVEL

Benign

0.016

Sift

Benign

0.51

Sift4G

Benign

0.53

Polyphen

0.0

Vest4

0.089

MVP

0.23

MPC

0.18

ClinPred

0.00079

GERP RS

-3.8

Varity_R

0.026

gMVP

0.17

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