rs141292909

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 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 0.000088 ( 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

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 links:

SRPX2 (HGNC:):

SRPX2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 207384.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRPX2	NM_014467.3 linkuse as main transcript	c.1199A>G	p.Asn400Ser	missense_variant	10/11	ENST00000373004.5	NP_055282.1	O60687

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SRPX2	ENST00000373004.5 linkuse as main transcript	c.1199A>G	p.Asn400Ser	missense_variant	10/11	1	NM_014467.3	ENSP00000362095.3	O60687
SRPX2	ENST00000640282.1 linkuse as main transcript	c.142-1456A>G		intron_variant		5		ENSP00000491188.1	A0A1W2PNZ6
SRPX2	ENST00000638920.1 linkuse as main transcript	n.1202A>G		non_coding_transcript_exon_variant	9/10	5

Frequencies

GnomAD3 genomes

AF:

0.0000884

AC:

AN:

90512

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

20302

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

GnomAD3 exomes

AF:

0.0000234

AC:

AN:

170754

Hom.:

AF XY:

0.00

AC XY:

AN XY:

56556

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 SAS 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

Gnomad4 AFR exome

AF:

0.000231

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000193

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000680

Gnomad4 OTH exome

AF:

0.0000288

GnomAD4 genome

AF:

0.0000884

AC:

AN:

90512

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

20302

show subpopulations

Gnomad4 AFR

AF:

0.000287

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000212

Gnomad4 OTH

AF:

0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2022

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. 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. 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. This variant is present in population databases (rs141292909, gnomAD 0.03%). 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). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 13, 2018

- -

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over