rs149051060

chrX-100667342-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_014467.3(SRPX2):c.1030C>A(p.Leu344Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000259 in 1,209,692 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 91 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., 40 hem., cov: 24)
  • Exomes 𝑓: 0.00015 (0 hom. 51 hem.)
• Consequence: SRPX2 NM_014467.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:4
• Conservation: PhyloP100: 5.66

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01242426).
• BS2: High Hemizygotes in GnomAd at 40 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRPX2	NM_014467.3	c.1030C>A	p.Leu344Ile	missense_variant	9/11	ENST00000373004.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRPX2	ENST00000373004.5	c.1030C>A	p.Leu344Ile	missense_variant	9/11	1	NM_014467.3	P1

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 145 AN: 111925 Hom.: 0 Cov.: 24 AF XY: 0.00117 AC XY: 40 AN XY: 34093

Gnomad AFR AF: 0.00424

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

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: 0.0000939

Gnomad OTH AF: 0.000661

GnomAD3 exomes AF: 0.000343 AC: 63 AN: 183472 Hom.: 0 AF XY: 0.000265 AC XY: 18 AN XY: 67914

Gnomad AFR exome AF: 0.00395

Gnomad AMR exome AF: 0.000219

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: 0.0000488

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000153 AC: 168 AN: 1097714 Hom.: 0 Cov.: 31 AF XY: 0.000140 AC XY: 51 AN XY: 363074

Gnomad4 AFR exome AF: 0.00394

Gnomad4 AMR exome AF: 0.000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000380

Gnomad4 OTH exome AF: 0.000326

GnomAD4 genome AF: 0.00129 AC: 145 AN: 111978 Hom.: 0 Cov.: 24 AF XY: 0.00117 AC XY: 40 AN XY: 34156

Gnomad4 AFR AF: 0.00423

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000939

Gnomad4 OTH AF: 0.000652

Alfa AF: 0.000141 Hom.: 3

Bravo AF: 0.00146

ESP6500AA AF: 0.00495 AC: 19

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rolandic epilepsy, intellectual disability, and speech dyspraxia, X-linked Pathogenic:1 Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Aug 31, 2022	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2014	p.Leu344Ile (CTC>ATC): c.1030 C>A in exon 9 in the SRPX2 gene (NM_014467.2). The L344I variant in the SRPX2 gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The L344I variant has been identified at low frequency in African Americans (0.49%, 19/3835 alleles) by the NHLBI Exome Sequencing Project and was not observed in the homozygous state in any individual within this population. The L344I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret L344I as a variant of unknown significance. The variant is found in CHILD-EPI,EPILEPSY panel(s). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2015	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 08, 2018

- -

SRPX2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.062	T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.89	N;.
REVEL	Benign	0.19
Sift	Uncertain	0.010	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.61
MVP		0.38
MPC		0.70
ClinPred		0.021	T
GERP RS		5.3
Varity_R		0.66
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs149051060; hg19: chrX-99922339;