chrX-100670844-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_014467.3(SRPX2):c.1255G>A(p.Val419Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,209,468 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)
Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )
Consequence
SRPX2
NM_014467.3 missense
NM_014467.3 missense
Scores
4
5
Clinical Significance
Conservation
PhyloP100: 4.77
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.35753813).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SRPX2 | NM_014467.3 | c.1255G>A | p.Val419Met | missense_variant | 11/11 | ENST00000373004.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SRPX2 | ENST00000373004.5 | c.1255G>A | p.Val419Met | missense_variant | 11/11 | 1 | NM_014467.3 | P1 | |
SRPX2 | ENST00000640282.1 | c.179G>A | p.Gly60Asp | missense_variant | 3/3 | 5 | |||
SRPX2 | ENST00000638920.1 | n.1258G>A | non_coding_transcript_exon_variant | 10/10 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00000899 AC: 1AN: 111240Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33438
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GnomAD3 exomes AF: 0.0000109 AC: 2AN: 183200Hom.: 0 AF XY: 0.0000148 AC XY: 1AN XY: 67690
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GnomAD4 exome AF: 0.00000182 AC: 2AN: 1098228Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1AN XY: 363582
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GnomAD4 genome AF: 0.00000899 AC: 1AN: 111240Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33438
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 02, 2014 | - - |
Rolandic epilepsy, intellectual disability, and speech dyspraxia, X-linked Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SRPX2 protein function. ClinVar contains an entry for this variant (Variation ID: 212309). This variant has not been reported in the literature in individuals affected with SRPX2-related conditions. This variant is present in population databases (rs797046012, gnomAD 0.004%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 419 of the SRPX2 protein (p.Val419Met). - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Benign
T
MutationTaster
Benign
D
ClinPred
D
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at