Genetic Variant NM_002518.4:c.631A>G (chr2-100964090-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002518.4(NPAS2):c.631A>G(p.Thr211Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000861 in 1,613,794 control chromosomes in the GnomAD database, including 1 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 0.00048 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00090 ( 1 hom. )

Consequence

NPAS2
NM_002518.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0620

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010822952).

BS2

High AC in GnomAd4 at 73 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPAS2	NM_002518.4 link	c.631A>G	p.Thr211Ala	missense_variant	Exon 8 of 21	ENST00000335681.10	NP_002509.2	Q99743A2I2P5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPAS2	ENST00000335681.10 link	c.631A>G	p.Thr211Ala	missense_variant	Exon 8 of 21	1	NM_002518.4	ENSP00000338283.5	Q99743
NPAS2	ENST00000448812.5 link	c.566-4191A>G		intron_variant	Intron 5 of 6	5		ENSP00000388528.1	H7BZA3
NPAS2	ENST00000486017.5 link	n.678A>G		non_coding_transcript_exon_variant	Exon 7 of 7	3
NPAS2	ENST00000492373.1 link	n.408A>G		non_coding_transcript_exon_variant	Exon 5 of 6	4

Frequencies

GnomAD3 genomes

AF:

0.000481

AC:

AN:

151892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000968

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000971

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000433

AC:

109

AN:

251446

Hom.:

AF XY:

0.000464

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000791

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000901

AC:

1317

AN:

1461784

Hom.:

Cov.:

AF XY:

0.000862

AC XY:

627

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.00110

Gnomad4 OTH exome

AF:

0.000894

GnomAD4 genome

AF:

0.000480

AC:

AN:

152010

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000971

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000865

Hom.:

Bravo

AF:

0.000586

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000404

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000830

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.14

DANN

Benign

0.70

DEOGEN2

Benign

0.039

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.53

M_CAP

Benign

0.0042

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.49

PrimateAI

Benign

0.38

PROVEAN

Benign

0.50

REVEL

Benign

0.044

Sift

Benign

0.76

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.12

MVP

0.28

MPC

0.72

ClinPred

0.0051

GERP RS

-3.5

Varity_R

0.029

gMVP

0.53

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over