6-33419822-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The XM_047419455.1(SYNGAP1):c.-18+1440G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 153,928 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (21 hom., cov: 30)
  • Exomes 𝑓: 0.0054 (0 hom.)
• Consequence: SYNGAP1 XM_047419455.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.54

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 6-33419822-G-C is Benign according to our data. Variant chr6-33419822-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1204001.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0119 (1802/151894) while in subpopulation AFR AF= 0.0212 (877/41404). AF 95% confidence interval is 0.02. There are 21 homozygotes in gnomad4. There are 919 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 1803 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNGAP1	XM_047419455.1	c.-18+1440G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNGAP1	ENST00000637194.1	n.39+123G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1803 AN: 151776 Hom.: 21 Cov.: 30

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.00735

Gnomad SAS AF: 0.0125

Gnomad FIN AF: 0.00199

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00802

Gnomad OTH AF: 0.00960

GnomAD4 exome AF: 0.00541 AC: 11 AN: 2034 Hom.: 0 Cov.: 0 AF XY: 0.00618 AC XY: 8 AN XY: 1294

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0152

Gnomad4 SAS exome AF: 0.00836

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00356

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0119 AC: 1802 AN: 151894 Hom.: 21 Cov.: 30 AF XY: 0.0124 AC XY: 919 AN XY: 74270

Gnomad4 AFR AF: 0.0212

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.00736

Gnomad4 SAS AF: 0.0125

Gnomad4 FIN AF: 0.00199

Gnomad4 NFE AF: 0.00803

Gnomad4 OTH AF: 0.00950

Alfa AF: 0.00963 Hom.: 1

Bravo AF: 0.0134

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	17
Dann	Benign	0.84

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs9688415; hg19: chr6-33387599;