9-136208879-G-T

Variant names:

• chr9-136208879-G-T
• NM_181701.4:c.1946C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181701.4(QSOX2):​c.1946C>A​(p.Ala649Glu) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A649T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: QSOX2 NM_181701.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.358
• Publications: 0 publications found

Genes affected

QSOX2 (HGNC:30249): (quiescin sulfhydryl oxidase 2) QSOX2 is a member of the sulfhydryl oxidase/quiescin-6 (Q6) family (QSOX1; MIM 603120) that regulates the sensitization of neuroblastoma cells for IFN-gamma (IFNG; MIM 147570)-induced cell death (Wittke et al., 2003 [PubMed 14633699]).[supplied by OMIM, Jun 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.085419655).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
QSOX2	NM_181701.4	c.1946C>A	p.Ala649Glu	missense_variant	Exon 12 of 12	ENST00000358701.10	NP_859052.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
QSOX2	ENST00000358701.10	c.1946C>A	p.Ala649Glu	missense_variant	Exon 12 of 12	2	NM_181701.4	ENSP00000351536.5
QSOX2	ENST00000706609.1	n.1132C>A		non_coding_transcript_exon_variant	Exon 6 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1946C>A (p.A649E) alteration is located in exon 12 (coding exon 12) of the QSOX2 gene. This alteration results from a C to A substitution at nucleotide position 1946, causing the alanine (A) at amino acid position 649 to be replaced by a glutamic acid (E). 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	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.14
DANN	Benign	0.69
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.36
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.040
Sift	Benign	0.077	T
Sift4G	Benign	0.77	T
Polyphen		0.63	P
Vest4		0.12
MutPred		0.46		Gain of disorder (P = 0.0384);
MVP		0.048
MPC		0.37
ClinPred		0.17	T
GERP RS		-9.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.60
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

hg19: chr9-139100725;