rs761691865

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_006772.3(SYNGAP1):c.2324G>A(p.Arg775Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 779,186 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R775L) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

SYNGAP1
NM_006772.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.54

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18834099).

BP6

Variant 6-33442482-G-A is Benign according to our data. Variant chr6-33442482-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212350.

BS2

High AC in GnomAdExome4 at 10 AD,Unknown gene.

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	UniProt
SYNGAP1	NM_006772.3	MANE Select	c.2324G>A	p.Arg775Gln	missense	Exon 14 of 19	NP_006763.2	A0A1U9X8L0
SYNGAP1	NM_001130066.2		c.2295-407G>A		intron	N/A	NP_001123538.1	B7ZCA0
SYNGAP1-AS1	NR_174954.1		n.329+4124C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYNGAP1	ENST00000646630.1	MANE Select	c.2324G>A	p.Arg775Gln	missense	Exon 14 of 19	ENSP00000496007.1	Q96PV0-1
SYNGAP1	ENST00000644458.1		c.2324G>A	p.Arg775Gln	missense	Exon 14 of 19	ENSP00000495541.1	A0A2R8Y6T2
SYNGAP1	ENST00000418600.7	TSL:5	c.2324G>A	p.Arg775Gln	missense	Exon 14 of 19	ENSP00000403636.3	Q96PV0-2

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151500

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

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

250572

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000159

AC:

AN:

627686

Hom.:

Cov.:

AF XY:

0.0000205

AC XY:

AN XY:

342074

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17692

American (AMR)

AF:

0.0000229

AC:

AN:

43740

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20984

East Asian (EAS)

AF:

0.00

AC:

AN:

36070

South Asian (SAS)

AF:

0.0000287

AC:

AN:

69798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4148

European-Non Finnish (NFE)

AF:

0.0000143

AC:

AN:

350092

Other (OTH)

AF:

0.0000604

AC:

AN:

33088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151500

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73974

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41146

American (AMR)

AF:

0.00

AC:

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67886

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000480

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability, autosomal dominant 5 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.043

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.0077

MetaRNN

Benign

0.19

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

1.5

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.63

REVEL

Benign

0.085

Sift

Benign

0.11

Sift4G

Benign

0.57

Polyphen

0.97

Vest4

0.55

MutPred

0.28

Loss of MoRF binding (P = 0.0076)

MVP

0.17

MPC

1.5

ClinPred

0.24

GERP RS

4.3

Varity_R

0.091

gMVP

0.33

Mutation Taster

=93/7

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over