rs147757229

chrX-100666892-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_014467.3(SRPX2):c.920A>G(p.Gln307Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000298 in 1,209,246 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.000015 (0 hom. 4 hem.)
• Consequence: SRPX2 NM_014467.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.85

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRPX2	NM_014467.3	c.920A>G	p.Gln307Arg	missense_variant	8/11	ENST00000373004.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRPX2	ENST00000373004.5	c.920A>G	p.Gln307Arg	missense_variant	8/11	1	NM_014467.3	P1

Frequencies

GnomAD3 genomes AF: 0.000160 AC: 18 AN: 112407 Hom.: 0 Cov.: 23 AF XY: 0.000116 AC XY: 4 AN XY: 34573

Gnomad AFR AF: 0.000550

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000369

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000501 AC: 9 AN: 179783 Hom.: 0 AF XY: 0.0000307 AC XY: 2 AN XY: 65059

Gnomad AFR exome AF: 0.000626

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: 0.00

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.0000155 AC: 17 AN: 1096786 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 4 AN XY: 362382

Gnomad4 AFR exome AF: 0.000455

Gnomad4 AMR exome AF: 0.0000854

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: 0.00

Gnomad4 OTH exome AF: 0.0000435

GnomAD4 genome AF: 0.000169 AC: 19 AN: 112460 Hom.: 0 Cov.: 23 AF XY: 0.000144 AC XY: 5 AN XY: 34636

Gnomad4 AFR AF: 0.000581

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000370

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000231 Hom.: 1

Bravo AF: 0.000193

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000495 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 27, 2014

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 20, 2021

This sequence change replaces glutamine with arginine at codon 307 of the SRPX2 protein (p.Gln307Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs147757229, ExAC 0.05%). This variant has not been reported in the literature in individuals affected with SRPX2-related conditions. ClinVar contains an entry for this variant (Variation ID: 198858). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Uncertain	0.020
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.066	T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.00030	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.74
MVP		0.69
MPC		0.51
ClinPred		0.20	T
GERP RS		5.3
Varity_R		0.72
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147757229; hg19: chrX-99921889;