6-33432704-G-C

Variant names:

• chr6-33432704-G-C
• rs759426721
• NM_006772.3:c.407G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006772.3(SYNGAP1):​c.407G>C​(p.Arg136Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R136W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27
• Publications: 0 publications found

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]

SYNGAP1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• SYNGAP1-related developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.407G>C	p.Arg136Pro	missense_variant	Exon 5 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.407G>C	p.Arg136Pro	missense_variant	Exon 5 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.407G>C	p.Arg136Pro	missense_variant	Exon 5 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.407G>C	p.Arg136Pro	missense_variant	Exon 5 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.407G>C	p.Arg136Pro	missense_variant	Exon 5 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.230G>C	p.Arg77Pro	missense_variant	Exon 3 of 17			ENSP00000494861.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Uncertain:1

Mar 05, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This sequence change replaces arginine with proline at codon 136 of the SYNGAP1 protein (p.Arg136Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SYNGAP1-related disease. 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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;D;.;.;.;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.3	M;M;.;.;M;M;.;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.7	.;.;.;D;.;D;D;.
REVEL	Benign	0.28
Sift	Uncertain	0.022	.;.;.;D;.;D;D;.
Sift4G	Uncertain	0.0020	.;D;.;D;D;D;D;.
Polyphen		0.91	P;P;.;D;P;.;.;.
Vest4		0.58, 0.59, 0.62, 0.59
MutPred		0.23		Loss of methylation at R136 (P = 0.0363);Loss of methylation at R136 (P = 0.0363);Loss of methylation at R136 (P = 0.0363);Loss of methylation at R136 (P = 0.0363);Loss of methylation at R136 (P = 0.0363);Loss of methylation at R136 (P = 0.0363);.;.;
MVP		0.33
MPC		2.5
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.76
gMVP		0.84
Mutation Taster		=22/78	disease causing

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

Other links and lift over

dbSNP: rs759426721; hg19: chr6-33400481;