rs2305160

Positions:

• chr2-100974842-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002518.4(NPAS2):​c.1180A>G​(p.Thr394Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.683 in 1,613,724 control chromosomes in the GnomAD database, including 380,103 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.74 (42959 hom., cov: 33)
  • Exomes 𝑓: 0.68 (337144 hom.)
• Consequence: NPAS2 NM_002518.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.590

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.0232136E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPAS2	NM_002518.4	c.1180A>G	p.Thr394Ala	missense_variant	13/21	ENST00000335681.10	NP_002509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPAS2	ENST00000335681.10	c.1180A>G	p.Thr394Ala	missense_variant	13/21	1	NM_002518.4	ENSP00000338283.5

Frequencies

GnomAD3 genomes AF: 0.744 AC: 113038 AN: 151992 Hom.: 42911 Cov.: 33

Gnomad AFR AF: 0.897

Gnomad AMI AF: 0.781

Gnomad AMR AF: 0.729

Gnomad ASJ AF: 0.659

Gnomad EAS AF: 0.839

Gnomad SAS AF: 0.732

Gnomad FIN AF: 0.729

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.654

Gnomad OTH AF: 0.725

GnomAD3 exomes AF: 0.707 AC: 177742 AN: 251262 Hom.: 63648 AF XY: 0.702 AC XY: 95266 AN XY: 135774

Gnomad AFR exome AF: 0.902

Gnomad AMR exome AF: 0.708

Gnomad ASJ exome AF: 0.670

Gnomad EAS exome AF: 0.847

Gnomad SAS exome AF: 0.715

Gnomad FIN exome AF: 0.722

Gnomad NFE exome AF: 0.656

Gnomad OTH exome AF: 0.690

GnomAD4 exome AF: 0.676 AC: 988604 AN: 1461614 Hom.: 337144 Cov.: 50 AF XY: 0.676 AC XY: 491746 AN XY: 727110

Gnomad4 AFR exome AF: 0.906

Gnomad4 AMR exome AF: 0.711

Gnomad4 ASJ exome AF: 0.669

Gnomad4 EAS exome AF: 0.830

Gnomad4 SAS exome AF: 0.711

Gnomad4 FIN exome AF: 0.716

Gnomad4 NFE exome AF: 0.657

Gnomad4 OTH exome AF: 0.696

GnomAD4 genome AF: 0.744 AC: 113143 AN: 152110 Hom.: 42959 Cov.: 33 AF XY: 0.748 AC XY: 55597 AN XY: 74336

Gnomad4 AFR AF: 0.898

Gnomad4 AMR AF: 0.728

Gnomad4 ASJ AF: 0.659

Gnomad4 EAS AF: 0.839

Gnomad4 SAS AF: 0.730

Gnomad4 FIN AF: 0.729

Gnomad4 NFE AF: 0.654

Gnomad4 OTH AF: 0.728

Alfa AF: 0.677 Hom.: 90032

Bravo AF: 0.751

TwinsUK AF: 0.648 AC: 2403

ALSPAC AF: 0.663 AC: 2556

ESP6500AA AF: 0.893 AC: 3934

ESP6500EA AF: 0.673 AC: 5788

ExAC AF: 0.707 AC: 85827

Asia WGS AF: 0.800 AC: 2782 AN: 3478

EpiCase AF: 0.668

EpiControl AF: 0.666

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.13
DANN	Benign	0.41
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.029	T
MetaRNN	Benign	7.0e-7	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.075	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.013
Sift	Benign	0.85	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.026
MPC		0.28
ClinPred		0.00058	T
GERP RS		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.013
gMVP		0.31

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: rs2305160; hg19: chr2-101591304; COSMIC: COSV59555566; COSMIC: COSV59555566;