rs141292909

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_014467.3(SRPX2):c.1199A>G(p.Asn400Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000196 in 1,020,097 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000088 ( 0 hom., 0 hem., cov: 18)

Exomes 𝑓: 0.000013 ( 0 hom. 4 hem. )

Consequence

SRPX2
NM_014467.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.843

Publications

1 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02388984).

BP6

Variant X-100669351-A-G is Benign according to our data. Variant chrX-100669351-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 207384.

BS2

High AC in GnomAd4 at 8 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRPX2	NM_014467.3 link	c.1199A>G	p.Asn400Ser	missense_variant	Exon 10 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.1199A>G	p.Asn400Ser	missense_variant	Exon 10 of 11	1	NM_014467.3	ENSP00000362095.3	O60687
SRPX2	ENST00000638920.1 link	n.1202A>G		non_coding_transcript_exon_variant	Exon 9 of 10	5
SRPX2	ENST00000640282.1 link	c.142-1456A>G		intron_variant	Intron 2 of 2	5		ENSP00000491188.1	A0A1W2PNZ6

Frequencies

GnomAD3 genomes

AF:

0.0000884

AC:

AN:

90512

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000287

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000212

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000234

AC:

AN:

170754

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000241

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000134

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000129

AC:

AN:

929585

Hom.:

Cov.:

AF XY:

0.0000132

AC XY:

AN XY:

303159

show subpopulations

African (AFR)

AF:

0.000231

AC:

AN:

21689

American (AMR)

AF:

0.00

AC:

AN:

29566

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13432

East Asian (EAS)

AF:

0.00

AC:

AN:

14197

South Asian (SAS)

AF:

0.0000193

AC:

AN:

51741

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25714

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3110

European-Non Finnish (NFE)

AF:

0.00000680

AC:

AN:

735361

Other (OTH)

AF:

0.0000288

AC:

AN:

34775

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000884

AC:

AN:

90512

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

20302

show subpopulations

African (AFR)

AF:

0.000287

AC:

AN:

24428

American (AMR)

AF:

0.00

AC:

AN:

7537

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2346

East Asian (EAS)

AF:

0.00

AC:

AN:

2342

South Asian (SAS)

AF:

0.00

AC:

AN:

1325

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

186

European-Non Finnish (NFE)

AF:

0.0000212

AC:

AN:

47073

Other (OTH)

AF:

0.00

AC:

AN:

1203

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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:

0.0000434

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:1

Aug 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 400 of the SRPX2 protein (p.Asn400Ser). This variant is present in population databases (rs141292909, gnomAD 0.03%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 207384). This variant has not been reported in the literature in individuals affected with SRPX2-related conditions. -

not provided

Benign:1

Nov 13, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-1.0

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.042

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.67

M_CAP

Benign

0.0076

MetaRNN

Benign

0.024

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

PhyloP100

0.84

PrimateAI

Benign

0.32

PROVEAN

Benign

0.40

REVEL

Benign

0.050

Sift

Benign

0.59

Sift4G

Benign

0.66

Polyphen

0.0

Vest4

0.097

MVP

0.26

MPC

0.12

ClinPred

0.0030

GERP RS

-2.5

Varity_R

0.031

gMVP

0.11

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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