19-45940351-C-T

Variant names:

• chr19-45940351-C-T
• rs756083426
• NM_002516.4:c.991G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002516.4(NOVA2):​c.991G>A​(p.Ala331Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000456 in 1,336,300 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (1 hom.)
• Consequence: NOVA2 NM_002516.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.69

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0555315).
• BP6: Variant 19-45940351-C-T is Benign according to our data. Variant chr19-45940351-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3239059.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOVA2	NM_002516.4	c.991G>A	p.Ala331Thr	missense_variant	Exon 4 of 4	ENST00000263257.6	NP_002507.1
NOVA2	XM_006723230.4	c.664G>A	p.Ala222Thr	missense_variant	Exon 5 of 5		XP_006723293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOVA2	ENST00000263257.6	c.991G>A	p.Ala331Thr	missense_variant	Exon 4 of 4	1	NM_002516.4	ENSP00000263257.4
NOVA2	ENST00000676183.1	c.1183G>A	p.Ala395Thr	missense_variant	Exon 4 of 4			ENSP00000501708.1

Frequencies

GnomAD3 genomes AF: 0.0000736 AC: 11 AN: 149506 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000666

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000208

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000119

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000122 AC: 6 AN: 49246 Hom.: 1 AF XY: 0.000101 AC XY: 3 AN XY: 29614

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000283

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000932

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000705

GnomAD4 exome AF: 0.0000421 AC: 50 AN: 1186794 Hom.: 1 Cov.: 30 AF XY: 0.0000429 AC XY: 25 AN XY: 582844

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000124

Gnomad4 FIN exome AF: 0.0000949

Gnomad4 NFE exome AF: 0.0000350

Gnomad4 OTH exome AF: 0.0000861

GnomAD4 genome AF: 0.0000736 AC: 11 AN: 149506 Hom.: 0 Cov.: 32 AF XY: 0.0000686 AC XY: 5 AN XY: 72876

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000666

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000208

Gnomad4 NFE AF: 0.000119

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000217 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NOVA2: PP2 -

Inborn genetic diseases Benign:1

Dec 25, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.67
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.056
Sift	Benign	0.64	T
Sift4G	Benign	0.43	T
Polyphen		0.0020	B
Vest4		0.12
MutPred		0.33		Gain of glycosylation at A331 (P = 0.0087);
MVP		0.23
ClinPred		0.034	T
GERP RS		-0.083
Varity_R		0.083
gMVP		0.47

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: rs756083426; hg19: chr19-46443609;