NM_014467.3:c.460C>G

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.460C>G(p.His154Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000518 in 1,209,271 control chromosomes in the GnomAD database, including 5 homozygotes. There are 157 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., 67 hem., cov: 24)

Exomes 𝑓: 0.00029 ( 3 hom. 90 hem. )

Consequence

SRPX2
NM_014467.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.55

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=0.012157857).

BP6

Variant X-100664878-C-G is Benign according to our data. Variant chrX-100664878-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 139323.

BS2

High AC in GnomAd4 at 307 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.460C>G	p.His154Asp	missense	Exon 5 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.460C>G	p.His154Asp	missense	Exon 5 of 11	ENSP00000362095.3	O60687
SRPX2	ENST00000638458.1	TSL:5	c.484C>G	p.His162Asp	missense	Exon 4 of 7	ENSP00000492168.1	A0A1W2PR88
SRPX2	ENST00000640889.1	TSL:5	c.460C>G	p.His154Asp	missense	Exon 5 of 7	ENSP00000492571.1	A0A1W2PRB1

Frequencies

GnomAD3 genomes

AF:

0.00274

AC:

308

AN:

112407

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00964

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000751

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:

0.0000188

Gnomad OTH

AF:

0.000660

GnomAD2 exomes

AF:

0.000750

AC:

134

AN:

178691

AF XY:

0.000452

show subpopulations

Gnomad AFR exome

AF:

0.00941

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000125

Gnomad OTH exome

AF:

0.000454

GnomAD4 exome

AF:

0.000292

AC:

320

AN:

1096812

Hom.:

Cov.:

AF XY:

0.000248

AC XY:

AN XY:

362378

show subpopulations

African (AFR)

AF:

0.00955

AC:

252

AN:

26392

American (AMR)

AF:

0.000427

AC:

AN:

35147

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19365

East Asian (EAS)

AF:

0.00

AC:

AN:

30196

South Asian (SAS)

AF:

0.000112

AC:

AN:

53714

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40242

Middle Eastern (MID)

AF:

0.000490

AC:

AN:

4078

European-Non Finnish (NFE)

AF:

0.0000107

AC:

AN:

841674

Other (OTH)

AF:

0.000783

AC:

AN:

46004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

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:

0.00273

AC:

307

AN:

112459

Hom.:

Cov.:

AF XY:

0.00194

AC XY:

AN XY:

34615

show subpopulations

African (AFR)

AF:

0.00959

AC:

297

AN:

30976

American (AMR)

AF:

0.000750

AC:

AN:

10662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2659

East Asian (EAS)

AF:

0.00

AC:

AN:

3550

South Asian (SAS)

AF:

0.00

AC:

AN:

2702

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6173

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53298

Other (OTH)

AF:

0.000651

AC:

AN:

1535

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.00192

Hom.:

Bravo

AF:

0.00317

ESP6500AA

AF:

0.0115

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000849

AC:

103

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.044

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.68

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.23

PhyloP100

3.5

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.12

REVEL

Benign

0.14

Sift

Benign

0.42

Sift4G

Benign

0.44

Polyphen

0.048

Vest4

0.62

MVP

0.64

MPC

0.33

ClinPred

0.012

GERP RS

3.7

Varity_R

0.080

gMVP

0.63

Mutation Taster

=82/18

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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