rs934177451

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_ModerateBP6

The NM_006772.3(SYNGAP1):c.2195G>A(p.Arg732Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,050 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SYNGAP1
NM_006772.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.40

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.20286155).

BP6

Variant 6-33441660-G-A is Benign according to our data. Variant chr6-33441660-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 537019.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3 link	c.2195G>A	p.Arg732Lys	missense_variant	Exon 13 of 19	ENST00000646630.1	NP_006763.2	Q96PV0-1A0A1U9X8L0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SYNGAP1	ENST00000646630.1 link	c.2195G>A	p.Arg732Lys	missense_variant	Exon 13 of 19		NM_006772.3	ENSP00000496007.1	Q96PV0-1
SYNGAP1	ENST00000644458.1 link	c.2195G>A	p.Arg732Lys	missense_variant	Exon 13 of 19			ENSP00000495541.1	A0A2R8Y6T2
SYNGAP1	ENST00000449372.7 link	c.2195G>A	p.Arg732Lys	missense_variant	Exon 13 of 18	5		ENSP00000416519.4	B7ZCA0
SYNGAP1	ENST00000418600.7 link	c.2195G>A	p.Arg732Lys	missense_variant	Exon 13 of 19	5		ENSP00000403636.3	Q96PV0-2
SYNGAP1	ENST00000645250.1 link	c.2018G>A	p.Arg673Lys	missense_variant	Exon 11 of 17			ENSP00000494861.1	A0A2R8YDS2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2195G>A (p.R732K) alteration is located in exon 13 (coding exon 13) of the SYNGAP1 gene. This alteration results from a G to A substitution at nucleotide position 2195, causing the arginine (R) at amino acid position 732 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Intellectual disability, autosomal dominant 5

Benign:1

Jan 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.053

T;T;.;.;.;.;.;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.96

.;D;D;D;D;D;D;D

M_CAP

Benign

0.0059

MetaRNN

Benign

0.20

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;.;.;L;L;.;.

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.66

.;.;.;N;.;N;N;.

REVEL

Benign

0.045

Sift

Benign

0.085

.;.;.;T;.;D;D;.

Sift4G

Benign

0.21

.;T;.;T;T;T;T;.

Polyphen

0.81

P;P;.;.;P;P;.;.

Vest4

0.27, 0.36, 0.26, 0.21

MutPred

0.27

Gain of methylation at R732 (P = 0.0127);Gain of methylation at R732 (P = 0.0127);Gain of methylation at R732 (P = 0.0127);Gain of methylation at R732 (P = 0.0127);Gain of methylation at R732 (P = 0.0127);Gain of methylation at R732 (P = 0.0127);.;.;

MVP

0.18

MPC

1.8

ClinPred

0.58

GERP RS

4.7

Varity_R

0.20

gMVP

0.74

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over