chr19-45940243-C-T

Variant names:

• chr19-45940243-C-T
• NM_002516.4:c.1099G>A
• NOVA2 p.Gly367Arg

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002516.4(NOVA2):​c.1099G>A​(p.Gly367Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NOVA2 NM_002516.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.93
• Publications: 0 publications found

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]

NOVA2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36955947).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002516.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOVA2	NM_002516.4	MANE Select	c.1099G>A	p.Gly367Arg	missense	Exon 4 of 4	NP_002507.1	Q9UNW9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOVA2	ENST00000263257.6	TSL:1 MANE Select	c.1099G>A	p.Gly367Arg	missense	Exon 4 of 4	ENSP00000263257.4	Q9UNW9
	NOVA2	ENST00000676183.1		c.1291G>A	p.Gly431Arg	missense	Exon 4 of 4	ENSP00000501708.1	A0A6Q8PFC2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 940284 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 443758

African (AFR) AF: 0.00 AC: 0 AN: 18000

American (AMR) AF: 0.00 AC: 0 AN: 4050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8046

East Asian (EAS) AF: 0.00 AC: 0 AN: 10620

South Asian (SAS) AF: 0.00 AC: 0 AN: 18502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11644

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2128

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 833674

Other (OTH) AF: 0.00 AC: 0 AN: 33620

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.9
PrimateAI	Pathogenic	0.97	D
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.12
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.031	D
Varity_R		0.23
gMVP		0.39
Mutation Taster		=93/7	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-46443501;