chr6-157982083-C-T

Position:

• chr6-157982083-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003898.4(SYNJ2):​c.122C>T​(p.Thr41Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000846 in 1,182,078 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: SYNJ2 NM_003898.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNJ2	NM_003898.4	c.122C>T	p.Thr41Met	missense_variant	1/27	ENST00000355585.9	NP_003889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNJ2	ENST00000355585.9	c.122C>T	p.Thr41Met	missense_variant	1/27	1	NM_003898.4	ENSP00000347792.4
SYNJ2	ENST00000640338.1	c.122C>T	p.Thr41Met	missense_variant	1/27	1		ENSP00000492532.1
SYNJ2	ENST00000367113.5	c.44C>T	p.Thr15Met	missense_variant	1/4	2		ENSP00000356080.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.46e-7 AC: 1 AN: 1182078 Hom.: 0 Cov.: 30 AF XY: 0.00000174 AC XY: 1 AN XY: 573312

Gnomad4 AFR exome AF: 0.0000422

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.: 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

Dec 28, 2022

The c.122C>T (p.T41M) alteration is located in exon 1 (coding exon 1) of the SYNJ2 gene. This alteration results from a C to T substitution at nucleotide position 122, causing the threonine (T) at amino acid position 41 to be replaced by a methionine (M). 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	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.70	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.4	L;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.13	N;.
REVEL	Uncertain	0.37
Sift	Uncertain	0.010	D;.
Sift4G	Uncertain	0.028	D;.
Polyphen		0.81	P;P
Vest4		0.19
MutPred		0.40		Loss of glycosylation at T41 (P = 0.0371);Loss of glycosylation at T41 (P = 0.0371);
MVP		0.85
MPC		0.41
ClinPred		0.94	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.15
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-158403115;