rs146063801

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_014467.3(SRPX2):c.737G>A(p.Arg246Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000768 in 1,210,298 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000059 ( 0 hom. 23 hem. )

Consequence

SRPX2
NM_014467.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.242

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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
epilepsy
Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

SRPX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025209785).

BP6

Variant X-100665613-G-A is Benign according to our data. Variant chrX-100665613-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 590220.

BS2

High AC in GnomAd4 at 28 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014467.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRPX2	NM_014467.3	MANE Select	c.737G>A	p.Arg246Gln	missense	Exon 7 of 11	NP_055282.1	O60687

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SRPX2	ENST00000373004.5	TSL:1 MANE Select	c.737G>A	p.Arg246Gln	missense	Exon 7 of 11	ENSP00000362095.3	O60687
SRPX2	ENST00000638458.1	TSL:5	c.761G>A	p.Arg254Gln	missense	Exon 6 of 7	ENSP00000492168.1	A0A1W2PR88
SRPX2	ENST00000638920.1	TSL:5	n.740G>A		non_coding_transcript_exon	Exon 6 of 10

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

112017

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000584

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000282

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000279

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000940

Gnomad OTH

AF:

0.000665

GnomAD2 exomes

AF:

0.000109

AC:

AN:

183252

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.000684

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000289

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000592

AC:

AN:

1098229

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

363583

show subpopulations

African (AFR)

AF:

0.000871

AC:

AN:

26402

American (AMR)

AF:

0.0000852

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.0000993

AC:

AN:

30206

South Asian (SAS)

AF:

0.000166

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000202

AC:

AN:

842113

Other (OTH)

AF:

0.000217

AC:

AN:

46098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

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:

0.000250

AC:

AN:

112069

Hom.:

Cov.:

AF XY:

0.0000876

AC XY:

AN XY:

34263

show subpopulations

African (AFR)

AF:

0.000583

AC:

AN:

30869

American (AMR)

AF:

0.000282

AC:

AN:

10643

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.000280

AC:

AN:

3575

South Asian (SAS)

AF:

0.00

AC:

AN:

2639

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6103

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000940

AC:

AN:

53167

Other (OTH)

AF:

0.000657

AC:

AN:

1522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000411

Hom.:

Bravo

AF:

0.000268

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

History of neurodevelopmental disorder (1)

Rolandic epilepsy, intellectual disability, and speech dyspraxia, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.98

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.037

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.0057

MetaRNN

Benign

0.025

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.65

PhyloP100

0.24

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.41

REVEL

Benign

0.060

Sift

Benign

0.27

Sift4G

Benign

0.45

Polyphen

0.0030

Vest4

0.044

MVP

0.32

MPC

0.18

ClinPred

0.014

GERP RS

0.040

Varity_R

0.081

gMVP

0.38

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over