6-157981971-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003898.4(SYNJ2):c.10A>G(p.Ser4Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000902 in 1,108,808 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.0e-7 (0 hom.)
• Consequence: SYNJ2 NM_003898.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

Genes affected

SYNJ2 (HGNC:11504): (synaptojanin 2) The gene is a member of the inositol-polyphosphate 5-phosphatase family. The encoded protein interacts with the ras-related C3 botulinum toxin substrate 1, which causes translocation of the encoded protein to the plasma membrane where it inhibits clathrin-mediated endocytosis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3735668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNJ2	NM_003898.4	c.10A>G	p.Ser4Gly	missense_variant	1/27	ENST00000355585.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNJ2	ENST00000355585.9	c.10A>G	p.Ser4Gly	missense_variant	1/27	1	NM_003898.4	P2
SYNJ2	ENST00000640338.1	c.10A>G	p.Ser4Gly	missense_variant	1/27	1		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.02e-7 AC: 1 AN: 1108808 Hom.: 0 Cov.: 30 AF XY: 0.00000189 AC XY: 1 AN XY: 528846

Gnomad4 AFR exome AF: 0.0000433

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Apr 29, 2022

The c.10A>G (p.S4G) alteration is located in exon 1 (coding exon 1) of the SYNJ2 gene. This alteration results from a A to G substitution at nucleotide position 10, causing the serine (S) at amino acid position 4 to be replaced by a glycine (G). 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	Benign	0.15
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.68	T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	0.63	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.58	N;.
REVEL	Benign	0.19
Sift	Benign	0.12	T;.
Sift4G	Benign	0.31	T;.
Polyphen		0.027	B;B
Vest4		0.18
MutPred		0.31		Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);
MVP		0.85
MPC		0.69
ClinPred		0.74	D
GERP RS		2.9
Varity_R		0.13
gMVP		0.33

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: rs748314269; hg19: chr6-158403003;