19-45940130-ACT-A

Position:

• chr19-45940130-ACT-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_002516.4(NOVA2):​c.1210_1211delAG​(p.Ser404fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NOVA2 NM_002516.4 frameshift
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.81

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.182 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOVA2	NM_002516.4	c.1210_1211delAG	p.Ser404fs	frameshift_variant	4/4	ENST00000263257.6	NP_002507.1
NOVA2	XM_006723230.4	c.883_884delAG	p.Ser295fs	frameshift_variant	5/5		XP_006723293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOVA2	ENST00000263257.6	c.1210_1211delAG	p.Ser404fs	frameshift_variant	4/4	1	NM_002516.4	ENSP00000263257.4
NOVA2	ENST00000676183.1	c.1402_1403delAG	p.Ser468fs	frameshift_variant	4/4			ENSP00000501708.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

NOVA2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2024

The NOVA2 c.1210_1211delAG variant is predicted to result in a frameshift and premature protein termination (p.Ser404Cysfs*11). This variant occurs in the last exon of the gene and is expected to escape nonsense mediated decay. To our knowledge, this variant has not been reported in the literature or in gnomAD, indicating it is rare. Premature termination variants in NOVA2 have been associated with disease (see fore example, Mattioli et al. 2020. PubMed ID: 32197073; Scala et al. 2022. PubMed ID: 35607920); however, all variants of this type have been upstream of this position. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

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: chr19-46443388;