6-33441326-C-T

Variant names:

• chr6-33441326-C-T
• rs1554121850
• NM_006772.3:c.2067C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_006772.3(SYNGAP1):​c.2067C>T​(p.Leu689Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,570 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 Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.235
• Publications: 0 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-AS1 (HGNC:53831): (SYNGAP1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 6-33441326-C-T is Benign according to our data. Variant chr6-33441326-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 436917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.235 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	NM_006772.3	MANE Select	c.2067C>T	p.Leu689Leu	synonymous	Exon 12 of 19	NP_006763.2
	SYNGAP1	NM_001130066.2		c.2067C>T	p.Leu689Leu	synonymous	Exon 12 of 18	NP_001123538.1
	SYNGAP1-AS1	NR_174954.1		n.330-3845G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.2067C>T	p.Leu689Leu	synonymous	Exon 12 of 19	ENSP00000496007.1
	SYNGAP1	ENST00000644458.1		c.2067C>T	p.Leu689Leu	synonymous	Exon 12 of 19	ENSP00000495541.1
	SYNGAP1	ENST00000449372.7	TSL:5	c.2067C>T	p.Leu689Leu	synonymous	Exon 12 of 18	ENSP00000416519.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461570 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727092

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jun 21, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intellectual disability, autosomal dominant 5 Benign:1

Feb 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.3
DANN	Benign	0.77
PhyloP100		-0.23

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: rs1554121850; hg19: chr6-33409103;