rs2305160

Variant names:

• chr2-100974842-A-G
• rs2305160
• NM_002518.4:c.1180A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 94 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: Benign. The variant received -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.

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.1180A>G	p.Thr394Ala	missense	Exon 13 of 21	NP_002509.2
	NPAS2-AS1	NR_110213.1		n.575+443T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPAS2	ENST00000335681.10	TSL:1 MANE Select	c.1180A>G	p.Thr394Ala	missense	Exon 13 of 21	ENSP00000338283.5	Q99743
	NPAS2	ENST00000474550.5	TSL:1	n.514A>G		non_coding_transcript_exon	Exon 2 of 9
	NPAS2	ENST00000906777.1		c.1180A>G	p.Thr394Ala	missense	Exon 14 of 22	ENSP00000576836.1

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

GnomAD2 exomes AF: 0.707 AC: 177742 AN: 251262 AF XY: 0.702

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 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

African (AFR) AF: 0.906 AC: 30334 AN: 33474

American (AMR) AF: 0.711 AC: 31789 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 17487 AN: 26136

East Asian (EAS) AF: 0.830 AC: 32945 AN: 39700

South Asian (SAS) AF: 0.711 AC: 61359 AN: 86250

European-Finnish (FIN) AF: 0.716 AC: 38247 AN: 53408

Middle Eastern (MID) AF: 0.763 AC: 4401 AN: 5768

European-Non Finnish (NFE) AF: 0.657 AC: 730036 AN: 1111782

Other (OTH) AF: 0.696 AC: 42006 AN: 60384

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

African (AFR) AF: 0.898 AC: 37292 AN: 41548

American (AMR) AF: 0.728 AC: 11125 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 2287 AN: 3472

East Asian (EAS) AF: 0.839 AC: 4290 AN: 5112

South Asian (SAS) AF: 0.730 AC: 3526 AN: 4828

European-Finnish (FIN) AF: 0.729 AC: 7712 AN: 10574

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.654 AC: 44452 AN: 67984

Other (OTH) AF: 0.728 AC: 1536 AN: 2110

Alfa AF: 0.683 Hom.: 172207

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 v4.9

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
PhyloP100		0.59
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
PromoterAI		0.0060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.013
gMVP		0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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