rs146051561

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:6

Conservation

PhyloP100: 0.893

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

rolandic epilepsy-speech dyspraxia syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
polymicrogyria, bilateral perisylvian, X-linked
Inheritance: XL Classification: LIMITED Submitted by: G2P
rolandic epilepsy, intellectual disability, and speech dyspraxia, X-linked
Inheritance: XL Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

SRPX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 130374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 136 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRPX2	NM_014467.3 link	c.1373G>A	p.Arg458Gln	missense_variant	Exon 11 of 11	ENST00000373004.5	NP_055282.1	O60687

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SRPX2	ENST00000373004.5 link	c.1373G>A	p.Arg458Gln	missense_variant	Exon 11 of 11	1	NM_014467.3	ENSP00000362095.3	O60687
SRPX2	ENST00000638920.1 link	n.1376G>A		non_coding_transcript_exon_variant	Exon 10 of 10	5
SRPX2	ENST00000640282.1 link	c.*108G>A		3_prime_UTR_variant	Exon 3 of 3	5		ENSP00000491188.1	A0A1W2PNZ6

Frequencies

GnomAD3 genomes

AF:

0.00121

AC:

135

AN:

111813

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000340

AC:

AN:

179344

AF XY:

0.000188

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 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

African (AFR)

AF:

0.00390

AC:

103

AN:

26393

American (AMR)

AF:

0.000485

AC:

AN:

35033

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19366

East Asian (EAS)

AF:

0.00

AC:

AN:

30176

South Asian (SAS)

AF:

0.00

AC:

AN:

53723

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40436

Middle Eastern (MID)

AF:

0.000968

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.0000238

AC:

AN:

841298

Other (OTH)

AF:

0.000434

AC:

AN:

46056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00122

AC:

136

AN:

111866

Hom.:

Cov.:

AF XY:

0.000910

AC XY:

AN XY:

34060

show subpopulations

African (AFR)

AF:

0.00406

AC:

125

AN:

30822

American (AMR)

AF:

0.000658

AC:

AN:

10631

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3534

South Asian (SAS)

AF:

0.00

AC:

AN:

2605

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53119

Other (OTH)

AF:

0.00266

AC:

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000516

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jan 08, 2018

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 21, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 05, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Sep 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SRPX2-related disorder

Benign:1

Jun 07, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

0.89

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

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over