Genetic Variant SRPX2:p.Pro181His (chrX-100665252-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_014467.3(SRPX2):c.542C>A(p.Pro181His) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,096,187 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P181R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0000018 ( 0 hom. 2 hem. )

Consequence

SRPX2
NM_014467.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.18

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

BS2

High Hemizygotes in GnomAdExome4 at 2 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.542C>A	p.Pro181His	missense	Exon 6 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.542C>A	p.Pro181His	missense	Exon 6 of 11	ENSP00000362095.3	O60687
SRPX2	ENST00000638458.1	TSL:5	c.566C>A	p.Pro189His	missense	Exon 5 of 7	ENSP00000492168.1	A0A1W2PR88
SRPX2	ENST00000640889.1	TSL:5	c.542C>A	p.Pro181His	missense	Exon 6 of 7	ENSP00000492571.1	A0A1W2PRB1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1096187

Hom.:

Cov.:

AF XY:

0.00000553

AC XY:

AN XY:

361699

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26382

American (AMR)

AF:

0.00

AC:

AN:

35082

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19346

East Asian (EAS)

AF:

0.00

AC:

AN:

30162

South Asian (SAS)

AF:

0.0000374

AC:

AN:

53430

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40393

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841227

Other (OTH)

AF:

0.00

AC:

AN:

46031

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

-0.11

MutationAssessor

Pathogenic

3.6

PhyloP100

7.2

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-6.9

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.69

MutPred

0.88

Loss of ubiquitination at K183 (P = 0.0589)

MVP

0.68

MPC

0.72

ClinPred

1.0

GERP RS

5.5

Varity_R

0.93

gMVP

0.78

Mutation Taster

=24/76

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over