19-45940221-G-C

Variant summary

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

The NM_002516.4(NOVA2):c.1121C>G(p.Ala374Gly) 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: NOVA2 NM_002516.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25

Genes affected

NOVA2 (HGNC:7887): (NOVA alternative splicing regulator 2) Enables sequence-specific mRNA binding activity. Involved in neuron differentiation and regulation of alternative mRNA splicing, via spliceosome. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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=0.07539725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOVA2	NM_002516.4	c.1121C>G	p.Ala374Gly	missense_variant	4/4	ENST00000263257.6
NOVA2	XM_006723230.4	c.794C>G	p.Ala265Gly	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOVA2	ENST00000263257.6	c.1121C>G	p.Ala374Gly	missense_variant	4/4	1	NM_002516.4	P1
NOVA2	ENST00000676183.1	c.1313C>G	p.Ala438Gly	missense_variant	4/4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.1121C>G (p.A374G) alteration is located in exon 4 (coding exon 4) of the NOVA2 gene. This alteration results from a C to G substitution at nucleotide position 1121, causing the alanine (A) at amino acid position 374 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	0.054
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	18
Dann	Benign	0.65
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.42	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.048
Sift	Benign	0.54	T
Sift4G	Benign	0.53	T
Polyphen		0.0010	B
Vest4		0.33
MutPred		0.34		Gain of relative solvent accessibility (P = 0.0023);
MVP		0.040
ClinPred		0.030	T
GERP RS		1.1
Varity_R		0.12
gMVP		0.29

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: rs991977647; hg19: chr19-46443479;