dbSNP rs11123857: NPAS2:n.5936A>G (chr2-100987350-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000474550.5(NPAS2):n.5936A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 152,268 control chromosomes in the GnomAD database, including 6,459 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.28 ( 6459 hom., cov: 34)

Exomes 𝑓: 0.13 ( 0 hom. )

Consequence

NPAS2
ENST00000474550.5 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.17

Publications

18 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPAS2	NM_002518.4 link	c.1630-729A>G		intron_variant	Intron 16 of 20	ENST00000335681.10	NP_002509.2	Q99743A2I2P5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPAS2	ENST00000474550.5 link	n.5936A>G	non_coding_transcript_exon_variant	Exon 5 of 9	1
NPAS2	ENST00000335681.10 link	c.1630-729A>G	intron_variant	Intron 16 of 20	1	NM_002518.4	ENSP00000338283.5	Q99743
NPAS2	ENST00000433408.1 link	c.124-729A>G	intron_variant	Intron 1 of 5	5		ENSP00000393396.1	H7C080
NPAS2	ENST00000450763.1 link	c.426+4973A>G	intron_variant	Intron 4 of 4	4		ENSP00000392125.1	H7BZY5

Frequencies

GnomAD3 genomes

AF:

0.277

AC:

42219

AN:

152142

Hom.:

6445

Cov.:

show subpopulations

Gnomad AFR

AF:

0.358

Gnomad AMI

AF:

0.228

Gnomad AMR

AF:

0.191

Gnomad ASJ

AF:

0.172

Gnomad EAS

AF:

0.00730

Gnomad SAS

AF:

0.122

Gnomad FIN

AF:

0.311

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.282

Gnomad OTH

AF:

0.245

GnomAD4 exome

AF:

0.125

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.250

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.278

AC:

42269

AN:

152260

Hom.:

6459

Cov.:

AF XY:

0.274

AC XY:

20375

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.358

AC:

14888

AN:

41532

American (AMR)

AF:

0.191

AC:

2921

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

597

AN:

3464

East Asian (EAS)

AF:

0.00732

AC:

AN:

5194

South Asian (SAS)

AF:

0.123

AC:

592

AN:

4830

European-Finnish (FIN)

AF:

0.311

AC:

3302

AN:

10616

Middle Eastern (MID)

AF:

0.184

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.282

AC:

19153

AN:

68006

Other (OTH)

AF:

0.244

AC:

516

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1548

3096

4645

6193

7741

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

422

844

1266

1688

2110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.270

Hom.:

8980

Bravo

AF:

0.272

Asia WGS

AF:

0.0910

AC:

320

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.035

(source)

DANN

Benign

0.40

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over