X-100646345-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014467.3(SRPX2):c.23G>A(p.Arg8Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,644 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SRPX2 NM_014467.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.507

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16898865).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRPX2	NM_014467.3	c.23G>A	p.Arg8Lys	missense_variant	2/11	ENST00000373004.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRPX2	ENST00000373004.5	c.23G>A	p.Arg8Lys	missense_variant	2/11	1	NM_014467.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000547 AC: 1 AN: 182760 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67290

Gnomad AFR exome AF: 0.0000760

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: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097644 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 363092

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 27, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	15
Dann	Uncertain	0.97
DEOGEN2	Benign	0.065	T;.;.
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.62	T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	0.96	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.24	N;.;.
REVEL	Benign	0.042
Sift	Benign	0.14	T;.;.
Sift4G	Benign	0.38	T;.;.
Polyphen		0.016	B;.;.
Vest4		0.15
MutPred		0.49		Gain of methylation at R8 (P = 0.0077);Gain of methylation at R8 (P = 0.0077);Gain of methylation at R8 (P = 0.0077);
MVP		0.56
MPC		0.16
ClinPred		0.025	T
GERP RS		3.0
Varity_R		0.15
gMVP		0.64

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: rs1382205262; hg19: chrX-99901342;