rs121918364

Variant names:

• chrX-100662227-A-C
• rs121918364
• NM_014467.3:c.215A>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014467.3(SRPX2):​c.215A>C​(p.Tyr72Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000413 in 1,209,383 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000041 (0 hom. 12 hem.)
• Consequence: SRPX2 NM_014467.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 2.15

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2066392).
• BS2: High Hemizygotes in GnomAdExome4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRPX2	NM_014467.3	c.215A>C	p.Tyr72Ser	missense_variant	Exon 4 of 11	ENST00000373004.5	NP_055282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRPX2	ENST00000373004.5	c.215A>C	p.Tyr72Ser	missense_variant	Exon 4 of 11	1	NM_014467.3	ENSP00000362095.3

Frequencies

GnomAD3 genomes AF: 0.0000449 AC: 5 AN: 111243 Hom.: 0 Cov.: 23 AF XY: 0.0000298 AC XY: 1 AN XY: 33519

Gnomad AFR AF: 0.0000327

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: 0.0000754

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000327 AC: 6 AN: 183411 Hom.: 0 AF XY: 0.0000442 AC XY: 3 AN XY: 67857

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000109

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: 0.0000366

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000410 AC: 45 AN: 1098140 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 12 AN XY: 363494

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000114

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: 0.0000451

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000449 AC: 5 AN: 111243 Hom.: 0 Cov.: 23 AF XY: 0.0000298 AC XY: 1 AN XY: 33519

Gnomad4 AFR AF: 0.0000327

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: 0.0000754

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000844 Hom.: 1

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Aug 06, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported to affect SRPX2 protein function (PMID: 16497722, 23831613, 18718938). 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. This variant has been observed in individual(s) with SRPX2-related conditions (PMID: 16497722). ClinVar contains an entry for this variant (Variation ID: 10776). This sequence change replaces tyrosine with serine at codon 72 of the SRPX2 protein (p.Tyr72Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine. This variant is present in population databases (rs121918364, ExAC 0.002%). -

Aug 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.042	T;.;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.76	N;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.13	N;.;.
REVEL	Benign	0.27
Sift	Benign	0.30	T;.;.
Sift4G	Benign	0.47	T;.;.
Polyphen		0.90	P;.;.
Vest4		0.82
MVP		0.91
MPC		0.81
ClinPred		0.18	T
GERP RS		5.1
Varity_R		0.28
gMVP		0.76

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: rs121918364; hg19: chrX-99917224;