1-85178220-C-T

Position:

• chr1-85178220-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032184.2(SYDE2):​c.2597G>A​(p.Arg866Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000489 in 1,432,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: SYDE2 NM_032184.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.77

Genes affected

SYDE2 (HGNC:25841): (synapse defective Rho GTPase homolog 2) Predicted to enable GTPase activator activity. Acts upstream of or within cell migration. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYDE2	NM_032184.2	c.2597G>A	p.Arg866Gln	missense_variant	4/7	ENST00000341460.6	NP_115560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYDE2	ENST00000341460.6	c.2597G>A	p.Arg866Gln	missense_variant	4/7	5	NM_032184.2	ENSP00000340594.5
SYDE2	ENST00000696556.1	c.3188G>A	p.Arg1063Gln	missense_variant	4/7			ENSP00000512715.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000489 AC: 7 AN: 1432462 Hom.: 0 Cov.: 30 AF XY: 0.00000282 AC XY: 2 AN XY: 709680

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: 0.00000365

Gnomad4 OTH exome AF: 0.0000506

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

The c.2597G>A (p.R866Q) alteration is located in exon 4 (coding exon 4) of the SYDE2 gene. This alteration results from a G to A substitution at nucleotide position 2597, causing the arginine (R) at amino acid position 866 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.099	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.73		Gain of ubiquitination at K863 (P = 0.0754);
MVP		0.68
MPC		0.57
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.69
gMVP		0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs1490904541; hg19: chr1-85643903; COSMIC: COSV105861409; COSMIC: COSV105861409;