2-100970993-C-A

Variant names:

• chr2-100970993-C-A
• rs1562313
• NM_002518.4:c.1059C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_002518.4(NPAS2):​c.1059C>A​(p.Tyr353*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPAS2 NM_002518.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.57
• Publications: 0 publications found

Genes affected

NPAS2 (HGNC:7895): (neuronal PAS domain protein 2) The protein encoded by this gene is a member of the basic helix-loop-helix (bHLH)-PAS family of transcription factors. A similar mouse protein may play a regulatory role in the acquisition of specific types of memory. It also may function as a part of a molecular clock operative in the mammalian forebrain. [provided by RefSeq, Jul 2008]

NPAS2-AS1 (HGNC:40408): (NPAS2 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002518.4. 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
	NPAS2	NM_002518.4	MANE Select	c.1059C>A	p.Tyr353*	stop_gained	Exon 12 of 21	NP_002509.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPAS2	ENST00000335681.10	TSL:1 MANE Select	c.1059C>A	p.Tyr353*	stop_gained	Exon 12 of 21	ENSP00000338283.5	Q99743
	NPAS2	ENST00000474550.5	TSL:1	n.393C>A		non_coding_transcript_exon	Exon 1 of 9
	NPAS2	ENST00000906777.1		c.1059C>A	p.Tyr353*	stop_gained	Exon 13 of 22	ENSP00000576836.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Benign	0.90
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.15	N
PhyloP100		-1.6
Vest4		0.94
ClinPred		0.95	D
GERP RS		-8.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=35/165	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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

dbSNP: rs1562313; hg19: chr2-101587455;