Genetic Variant PER2:p.Ala5Ser (chr2-238277924-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_022817.3(PER2):c.13G>T(p.Ala5Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000416 in 1,613,676 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A5V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 2 hom. )

Consequence

PER2
NM_022817.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.360

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

advanced sleep phase syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
advanced sleep phase syndrome 1
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

PER2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002901882).

BS2

High AC in GnomAd4 at 294 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PER2	NM_022817.3 link	c.13G>T	p.Ala5Ser	missense_variant	Exon 2 of 23	ENST00000254657.8	NP_073728.1	O15055-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PER2	ENST00000254657.8 link	c.13G>T	p.Ala5Ser	missense_variant	Exon 2 of 23	1	NM_022817.3	ENSP00000254657.3		O15055-1

Frequencies

GnomAD3 genomes

AF:

0.00193

AC:

294

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00656

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000696

AC:

172

AN:

247300

AF XY:

0.000425

show subpopulations

Gnomad AFR exome

AF:

0.00755

Gnomad AMR exome

AF:

0.00128

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000271

Gnomad OTH exome

AF:

0.000662

GnomAD4 exome

AF:

0.000258

AC:

377

AN:

1461306

Hom.:

Cov.:

AF XY:

0.000226

AC XY:

164

AN XY:

726896

show subpopulations

African (AFR)

AF:

0.00711

AC:

238

AN:

33466

American (AMR)

AF:

0.00114

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53236

Middle Eastern (MID)

AF:

0.000181

AC:

AN:

5528

European-Non Finnish (NFE)

AF:

0.0000567

AC:

AN:

1111958

Other (OTH)

AF:

0.000364

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00193

AC:

294

AN:

152370

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

122

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.00654

AC:

272

AN:

41588

American (AMR)

AF:

0.000914

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68038

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00102

Hom.:

Bravo

AF:

0.00225

ESP6500AA

AF:

0.00885

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000725

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.065

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.039

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.52

T;T

M_CAP

Benign

0.077

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;.

PhyloP100

-0.36

PrimateAI

Benign

0.23

PROVEAN

Benign

0.27

N;N

REVEL

Benign

0.0050

Sift

Benign

0.22

T;D

Sift4G

Benign

0.45

T;.

Polyphen

0.090

B;.

Vest4

0.024

MVP

0.32

MPC

0.35

ClinPred

0.011

GERP RS

-0.63

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.059

gMVP

0.049

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over