rs797046029

Variant names:

• chr6-33441325-TCTCCA-C
• rs797046029
• NM_006772.3:c.2066_2071delTCTCCAinsC

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PM2 PP2 PP5_Moderate

The NM_006772.3(SYNGAP1):​c.2066_2071delTCTCCAinsC​(p.Leu689ProfsTer49) variant causes a frameshift, 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SYNGAP1 NM_006772.3 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02

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

Verdict is Pathogenic. Variant got 13 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SYNGAP1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.6047 (above the threshold of 3.09). Trascript score misZ: 7.6762 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 5, SYNGAP1-related developmental and epileptic encephalopathy, myoclonic-astatic epilepsy.
• PP5: Variant 6-33441325-TCTCCA-C is Pathogenic according to our data. Variant chr6-33441325-TCTCCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 212349.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.2066_2071delTCTCCAinsC	p.Leu689ProfsTer49	frameshift_variant, missense_variant	Exon 12 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.2066_2071delTCTCCAinsC	p.Leu689ProfsTer49	frameshift_variant, missense_variant	Exon 12 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.2066_2071delTCTCCAinsC	p.Leu689ProfsTer49	frameshift_variant, missense_variant	Exon 12 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.2066_2071delTCTCCAinsC	p.Leu689ProfsTer49	frameshift_variant, missense_variant	Exon 12 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.2066_2071delTCTCCAinsC	p.Leu689ProfsTer49	frameshift_variant, missense_variant	Exon 12 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.1889_1894delTCTCCAinsC	p.Leu630ProfsTer49	frameshift_variant, missense_variant	Exon 10 of 17			ENSP00000494861.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Pathogenic:1

Jul 01, 2014

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797046029; hg19: chr6-33409102;