rs752176449
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_006772.3(SYNGAP1):c.163C>A(p.Gln55Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
SYNGAP1
NM_006772.3 missense
NM_006772.3 missense
Scores
1
4
9
Clinical Significance
Conservation
PhyloP100: 4.53
Genes affected
SYNGAP1 (HGNC:11497): (synaptic Ras GTPase activating protein 1) This gene encodes a Ras GTPase activating protein that is a member of the N-methyl-D-aspartate receptor complex. The N-terminal domain of the protein contains a Ras-GAP domain, a pleckstrin homology domain, and a C2 domain that may be involved in binding of calcium and phospholipids. The C-terminal domain consists of a ten histidine repeat region, serine and tyrosine phosphorylation sites, and a T/SXV motif required for postsynaptic scaffold protein interaction. The encoded protein negatively regulates Ras, Rap and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking to the postsynaptic membrane to regulate synaptic plasticity and neuronal homeostasis. Allelic variants of this gene are associated with intellectual disability and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, SYNGAP1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.24966493).
BS2
?
High AC in GnomAdExome4 at 23 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SYNGAP1 | NM_006772.3 | c.163C>A | p.Gln55Lys | missense_variant | 2/19 | ENST00000646630.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SYNGAP1 | ENST00000646630.1 | c.163C>A | p.Gln55Lys | missense_variant | 2/19 | NM_006772.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461864Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727230
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74362
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 28, 2015 | - - |
Intellectual disability, autosomal dominant 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2023 | This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 55 of the SYNGAP1 protein (p.Gln55Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SYNGAP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 520688). 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 SYNGAP1 protein function. 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.;.;.;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
M;M;.;.;M;M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Polyphen
B;B;.;P;B;.
Vest4
0.53, 0.57, 0.51
MutPred
Gain of methylation at Q55 (P = 0.0189);Gain of methylation at Q55 (P = 0.0189);Gain of methylation at Q55 (P = 0.0189);Gain of methylation at Q55 (P = 0.0189);Gain of methylation at Q55 (P = 0.0189);Gain of methylation at Q55 (P = 0.0189);
MVP
0.19
MPC
1.6
ClinPred
D
GERP RS
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gMVP
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