NM_006772.3:c.84T>C

Variant names:

• chr6-33423493-T-C
• rs142359891
• NM_006772.3:c.84T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006772.3(SYNGAP1):​c.84T>C​(p.Ser28Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,614,046 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (7 hom., cov: 32)
  • Exomes 𝑓: 0.012 (130 hom.)
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.33
• Publications: 4 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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• SYNGAP1-related developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 6-33423493-T-C is Benign according to our data. Variant chr6-33423493-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.33 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00779 (1186/152226) while in subpopulation NFE AF = 0.0123 (836/68014). AF 95% confidence interval is 0.0116. There are 7 homozygotes in GnomAd4. There are 554 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1186 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	NM_006772.3	MANE Select	c.84T>C	p.Ser28Ser	synonymous	Exon 2 of 19	NP_006763.2	A0A1U9X8L0
	SYNGAP1	NM_001130066.2		c.84T>C	p.Ser28Ser	synonymous	Exon 2 of 18	NP_001123538.1	B7ZCA0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.84T>C	p.Ser28Ser	synonymous	Exon 2 of 19	ENSP00000496007.1	Q96PV0-1
	SYNGAP1	ENST00000644458.1		c.84T>C	p.Ser28Ser	synonymous	Exon 2 of 19	ENSP00000495541.1	A0A2R8Y6T2
	SYNGAP1	ENST00000449372.7	TSL:5	c.84T>C	p.Ser28Ser	synonymous	Exon 2 of 18	ENSP00000416519.4	B7ZCA0

Frequencies

GnomAD3 genomes AF: 0.00780 AC: 1187 AN: 152108 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0171

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00690 AC: 1734 AN: 251476 AF XY: 0.00684

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0188

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00863

GnomAD4 exome AF: 0.0121 AC: 17645 AN: 1461820 Hom.: 130 Cov.: 31 AF XY: 0.0115 AC XY: 8340 AN XY: 727226

African (AFR) AF: 0.00194 AC: 65 AN: 33476

American (AMR) AF: 0.00195 AC: 87 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26134

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

South Asian (SAS) AF: 0.000580 AC: 50 AN: 86254

European-Finnish (FIN) AF: 0.0187 AC: 1001 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0143 AC: 15852 AN: 1111956

Other (OTH) AF: 0.00959 AC: 579 AN: 60392

GnomAD4 genome AF: 0.00779 AC: 1186 AN: 152226 Hom.: 7 Cov.: 32 AF XY: 0.00745 AC XY: 554 AN XY: 74412

African (AFR) AF: 0.00258 AC: 107 AN: 41544

American (AMR) AF: 0.00262 AC: 40 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4814

European-Finnish (FIN) AF: 0.0171 AC: 181 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0123 AC: 836 AN: 68014

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00875 Hom.: 4

Bravo AF: 0.00682

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Intellectual disability, autosomal dominant 5 (5)
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	SYNGAP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.71
PhyloP100		1.3
Mutation Taster		=100/0	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: rs142359891; hg19: chr6-33391270;