Genetic Variant NM_022817.3:c.3731G>A (chr2-238246412-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_022817.3(PER2):c.3731G>A(p.Gly1244Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,610,074 control chromosomes in the GnomAD database, including 33,535 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.15 ( 2413 hom., cov: 32)

Exomes 𝑓: 0.20 ( 31122 hom. )

Consequence

PER2
NM_022817.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.33

Variant links:

Genes affected

PER2 (HGNC:8846): (period circadian regulator 2) This gene is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. This gene is upregulated by CLOCK/ARNTL heterodimers but then represses this upregulation in a feedback loop using PER/CRY heterodimers to interact with CLOCK/ARNTL. Polymorphisms in this gene may increase the risk of getting certain cancers and have been linked to sleep disorders. [provided by RefSeq, Jan 2014]

PER2 links:

ENSG00000225057 (HGNC:):

ENSG00000225057 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00341174).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PER2	NM_022817.3 link	c.3731G>A	p.Gly1244Glu	missense_variant	Exon 23 of 23	ENST00000254657.8	NP_073728.1	O15055-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PER2	ENST00000254657.8 link	c.3731G>A	p.Gly1244Glu	missense_variant	Exon 23 of 23	1	NM_022817.3	ENSP00000254657.3	O15055-1
PER2	ENST00000707129.1 link	c.3731G>A	p.Gly1244Glu	missense_variant	Exon 23 of 23			ENSP00000516757.1	O15055-1
PER2	ENST00000707130.1 link	c.3731G>A	p.Gly1244Glu	missense_variant	Exon 23 of 23			ENSP00000516758.1	O15055-1
ENSG00000225057	ENST00000456601.1 link	n.1165C>T		non_coding_transcript_exon_variant	Exon 4 of 7	2

Frequencies

GnomAD3 genomes

AF:

0.154

AC:

23420

AN:

152024

Hom.:

2407

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0379

Gnomad AMI

AF:

0.173

Gnomad AMR

AF:

0.257

Gnomad ASJ

AF:

0.149

Gnomad EAS

AF:

0.269

Gnomad SAS

AF:

0.198

Gnomad FIN

AF:

0.113

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.195

Gnomad OTH

AF:

0.189

GnomAD3 exomes

AF:

0.206

AC:

51188

AN:

247886

Hom.:

6186

AF XY:

0.203

AC XY:

27205

AN XY:

134190

show subpopulations

Gnomad AFR exome

AF:

0.0338

Gnomad AMR exome

AF:

0.364

Gnomad ASJ exome

AF:

0.154

Gnomad EAS exome

AF:

0.279

Gnomad SAS exome

AF:

0.204

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.194

Gnomad OTH exome

AF:

0.200

GnomAD4 exome

AF:

0.199

AC:

290708

AN:

1457934

Hom.:

31122

Cov.:

AF XY:

0.199

AC XY:

144376

AN XY:

725186

show subpopulations

Gnomad4 AFR exome

AF:

0.0332

Gnomad4 AMR exome

AF:

0.354

Gnomad4 ASJ exome

AF:

0.153

Gnomad4 EAS exome

AF:

0.297

Gnomad4 SAS exome

AF:

0.206

Gnomad4 FIN exome

AF:

0.121

Gnomad4 NFE exome

AF:

0.199

Gnomad4 OTH exome

AF:

0.188

GnomAD4 genome

AF:

0.154

AC:

23425

AN:

152140

Hom.:

2413

Cov.:

AF XY:

0.154

AC XY:

11419

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0378

Gnomad4 AMR

AF:

0.257

Gnomad4 ASJ

AF:

0.149

Gnomad4 EAS

AF:

0.268

Gnomad4 SAS

AF:

0.198

Gnomad4 FIN

AF:

0.113

Gnomad4 NFE

AF:

0.195

Gnomad4 OTH

AF:

0.187

Alfa

AF:

0.192

Hom.:

7174

Bravo

AF:

0.162

TwinsUK

AF:

0.199

AC:

738

ALSPAC

AF:

0.191

AC:

738

ESP6500AA

AF:

0.0443

AC:

195

ESP6500EA

AF:

0.190

AC:

1633

ExAC

AF:

0.198

AC:

24072

Asia WGS

AF:

0.214

AC:

745

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

9.6

DANN

Benign

0.79

DEOGEN2

Benign

0.088

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.3

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.4

REVEL

Benign

0.099

Sift

Benign

0.94

Sift4G

Benign

1.0

Polyphen

0.020

Vest4

0.050

MPC

0.30

ClinPred

0.0028

GERP RS

2.9

Varity_R

0.035

gMVP

0.35

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