Genetic Variant SYNGAP1:p.Lys642Arg (chr6-33441184-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_006772.3(SYNGAP1):c.1925A>G(p.Lys642Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K642T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

SYNGAP1
NM_006772.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.30

Publications

0 publications found

Variant links:

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 links:

SYNGAP1-AS1 (HGNC:53831): (SYNGAP1 antisense RNA 1)

SYNGAP1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-33441184-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 437411.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006772.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SYNGAP1	NM_006772.3	MANE Select	c.1925A>G	p.Lys642Arg	missense	Exon 12 of 19	NP_006763.2
SYNGAP1	NM_001130066.2		c.1925A>G	p.Lys642Arg	missense	Exon 12 of 18	NP_001123538.1
SYNGAP1-AS1	NR_174954.1		n.330-3703T>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SYNGAP1	ENST00000646630.1	MANE Select	c.1925A>G	p.Lys642Arg	missense	Exon 12 of 19	ENSP00000496007.1
SYNGAP1	ENST00000644458.1		c.1925A>G	p.Lys642Arg	missense	Exon 12 of 19	ENSP00000495541.1
SYNGAP1	ENST00000449372.7	TSL:5	c.1925A>G	p.Lys642Arg	missense	Exon 12 of 18	ENSP00000416519.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.1

PhyloP100

9.3

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.32

Sift

Uncertain

0.013

Sift4G

Uncertain

0.035

Polyphen

0.0010

Vest4

0.74

MutPred

0.37

Loss of ubiquitination at K642 (P = 0.0092)

MVP

0.74

MPC

0.92

ClinPred

0.97

GERP RS

4.8

Varity_R

0.35

gMVP

0.87

Mutation Taster

=51/49

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over