rs768878991

Variant names:

• chr6-33443148-G-A
• rs768878991
• NM_006772.3:c.2596G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-33443148-G-A
• chr6-33443148-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Moderate BP6 BS2

The NM_006772.3(SYNGAP1):​c.2596G>A​(p.Val866Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V866L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.96
• 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-AS1 (HGNC:53831): (SYNGAP1 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12901923).
• BP6: Variant 6-33443148-G-A is Benign according to our data. Variant chr6-33443148-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 536995.
• BS2: High AC in GnomAdExome4 at 5 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.2596G>A	p.Val866Ile	missense_variant	Exon 15 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.2596G>A	p.Val866Ile	missense_variant	Exon 15 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.2596G>A	p.Val866Ile	missense_variant	Exon 15 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.2554G>A	p.Val852Ile	missense_variant	Exon 14 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.2596G>A	p.Val866Ile	missense_variant	Exon 15 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.2419G>A	p.Val807Ile	missense_variant	Exon 13 of 17			ENSP00000494861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250114 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461732 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727176

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111984

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Uncertain:1 Benign:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2020

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Sep 01, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V866I variant (also known as c.2596G>A), located in coding exon 15 of the SYNGAP1 gene, results from a G to A substitution at nucleotide position 2596. The valine at codon 866 is replaced by isoleucine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	T;T;.;.;.;.;.;.
Eigen	Benign	-0.032
Eigen_PC	Benign	-0.066
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.86	.;D;D;D;D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;.;.;L;L;.;.
PhyloP100		2.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.42	.;.;.;N;.;N;N;.
REVEL	Benign	0.059
Sift	Benign	0.060	.;.;.;T;.;T;T;.
Sift4G	Benign	0.12	.;T;.;T;T;T;T;.
Polyphen		0.96	D;D;.;.;P;P;.;.
Vest4		0.13, 0.12, 0.21, 0.14
MutPred		0.14		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);.;Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);.;.;
MVP		0.30
MPC		1.6
ClinPred		0.41	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.041
gMVP		0.38
Mutation Taster		=89/11	polymorphism

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: rs768878991; hg19: chr6-33410925;