14-81277544-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394390.1(STON2):c.1938G>T(p.Gln646His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STON2 NM_001394390.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0370

Genes affected

STON2 (HGNC:30652): (stonin 2) This gene encodes a protein which is a membrane protein involved in regulating endocytotic complexes. The protein product is described as one of the clathrin-associated sorting proteins, adaptor molecules which ensure specific proteins are internalized. The encoded protein has also been shown to participate in synaptic vesicle recycling through interaction with synaptotagmin 1 required for neurotransmission. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20829701).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STON2	NM_001394390.1	c.1938G>T	p.Gln646His	missense_variant	6/8	ENST00000614646.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STON2	ENST00000614646.5	c.1938G>T	p.Gln646His	missense_variant	6/8	5	NM_001394390.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Jul 06, 2021

The c.1767G>T (p.Q589H) alteration is located in exon 4 (coding exon 4) of the STON2 gene. This alteration results from a G to T substitution at nucleotide position 1767, causing the glutamine (Q) at amino acid position 589 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
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	17
Dann	Uncertain	1.0
Eigen	Benign	0.088
Eigen_PC	Benign	0.076
FATHMM_MKL	Benign	0.44	N
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.;L;L
MutationTaster	Benign	0.80	D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.42	N;.;.;N
REVEL	Benign	0.084
Sift	Benign	0.083	T;.;.;T
Sift4G	Benign	0.064	T;.;T;T
Polyphen		0.92	.;.;.;P
Vest4		0.13
MutPred		0.44		Gain of disorder (P = 0.1322);.;Gain of disorder (P = 0.1322);Gain of disorder (P = 0.1322);
MVP		0.082
MPC		0.097
ClinPred		0.51	D
GERP RS		4.0
Varity_R		0.074
gMVP		0.38

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: rs1020372129; hg19: chr14-81743888;