6-158059290-G-T

Variant summary

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

The NM_003898.4(SYNJ2):c.891G>T(p.Gln297His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 1,398,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: SYNJ2 NM_003898.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.947

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=0.28622133).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNJ2	NM_003898.4	c.891G>T	p.Gln297His	missense_variant	7/27	ENST00000355585.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNJ2	ENST00000355585.9	c.891G>T	p.Gln297His	missense_variant	7/27	1	NM_003898.4	P2
SYNJ2	ENST00000640338.1	c.891G>T	p.Gln297His	missense_variant	7/27	1		A2
SYNJ2	ENST00000638626.1	c.180G>T	p.Gln60His	missense_variant	6/26	1
SYNJ2	ENST00000485863.1	c.372G>T	p.Gln124His	missense_variant, NMD_transcript_variant	4/6	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000643 AC: 1 AN: 155522 Hom.: 0 AF XY: 0.0000122 AC XY: 1 AN XY: 81764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000166

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000358 AC: 5 AN: 1398214 Hom.: 0 Cov.: 29 AF XY: 0.00000435 AC XY: 3 AN XY: 689540

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: 0.00000463

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

Mar 02, 2023

The c.891G>T (p.Q297H) alteration is located in exon 7 (coding exon 7) of the SYNJ2 gene. This alteration results from a G to T substitution at nucleotide position 891, causing the glutamine (Q) at amino acid position 297 to be replaced by a histidine (H). 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	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;.
Eigen	Benign	0.031
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;T;D
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.065	N;N;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N;.;.
REVEL	Benign	0.14
Sift	Benign	0.061	T;.;.
Sift4G	Benign	0.066	T;.;.
Polyphen		0.78	P;P;.
Vest4		0.24
MutPred		0.61		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);.;
MVP		0.61
MPC		0.18
ClinPred		0.43	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.089
gMVP		0.40

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: rs1415332791; hg19: chr6-158480322;