2-238257022-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_022817.3(PER2):c.1965A>G(p.Ala655Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,613,266 control chromosomes in the GnomAD database, including 15,173 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1301 hom., cov: 33)

Exomes 𝑓: 0.13 ( 13872 hom. )

Consequence

PER2
NM_022817.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.552

Publications

30 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 2-238257022-T-C is Benign according to our data. Variant chr2-238257022-T-C is described in ClinVar as Benign. ClinVar VariationId is 1246724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.552 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PER2	NM_022817.3 link	c.1965A>G	p.Ala655Ala	synonymous_variant	Exon 17 of 23	ENST00000254657.8	NP_073728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PER2	ENST00000254657.8 link	c.1965A>G	p.Ala655Ala	synonymous_variant	Exon 17 of 23	1	NM_022817.3	ENSP00000254657.3
PER2	ENST00000707129.1 link	c.1965A>G	p.Ala655Ala	synonymous_variant	Exon 17 of 23			ENSP00000516757.1
PER2	ENST00000707130.1 link	c.1965A>G	p.Ala655Ala	synonymous_variant	Exon 17 of 23			ENSP00000516758.1

Frequencies

GnomAD3 genomes

AF:

0.114

AC:

17350

AN:

152152

Hom.:

1301

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0370

Gnomad AMI

AF:

0.184

Gnomad AMR

AF:

0.178

Gnomad ASJ

AF:

0.0885

Gnomad EAS

AF:

0.117

Gnomad SAS

AF:

0.0598

Gnomad FIN

AF:

0.161

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.143

Gnomad OTH

AF:

0.125

GnomAD2 exomes

AF:

0.129

AC:

32495

AN:

250950

AF XY:

0.125

show subpopulations

Gnomad AFR exome

AF:

0.0328

Gnomad AMR exome

AF:

0.203

Gnomad ASJ exome

AF:

0.0989

Gnomad EAS exome

AF:

0.107

Gnomad FIN exome

AF:

0.169

Gnomad NFE exome

AF:

0.141

Gnomad OTH exome

AF:

0.131

GnomAD4 exome

AF:

0.134

AC:

195981

AN:

1460996

Hom.:

13872

Cov.:

AF XY:

0.131

AC XY:

95391

AN XY:

726822

show subpopulations

African (AFR)

AF:

0.0304

AC:

1017

AN:

33480

American (AMR)

AF:

0.196

AC:

8750

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0958

AC:

2504

AN:

26134

East Asian (EAS)

AF:

0.120

AC:

4756

AN:

39688

South Asian (SAS)

AF:

0.0533

AC:

4600

AN:

86250

European-Finnish (FIN)

AF:

0.166

AC:

8807

AN:

52922

Middle Eastern (MID)

AF:

0.0708

AC:

408

AN:

5764

European-Non Finnish (NFE)

AF:

0.142

AC:

157768

AN:

1111670

Other (OTH)

AF:

0.122

AC:

7371

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

9324

18648

27971

37295

46619

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5608

11216

16824

22432

28040

<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:

0.114

AC:

17355

AN:

152270

Hom.:

1301

Cov.:

AF XY:

0.115

AC XY:

8531

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0369

AC:

1532

AN:

41556

American (AMR)

AF:

0.178

AC:

2728

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0885

AC:

307

AN:

3468

East Asian (EAS)

AF:

0.117

AC:

606

AN:

5182

South Asian (SAS)

AF:

0.0600

AC:

290

AN:

4832

European-Finnish (FIN)

AF:

0.161

AC:

1704

AN:

10602

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.143

AC:

9715

AN:

68014

Other (OTH)

AF:

0.125

AC:

263

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

825

1650

2475

3300

4125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

392

588

784

980

<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:

0.127

Hom.:

3567

Bravo

AF:

0.112

Asia WGS

AF:

0.0760

AC:

263

AN:

3478

EpiCase

AF:

0.135

EpiControl

AF:

0.138

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 01, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PER2-related disorder

Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.44

(source)

DANN

Benign

0.50

PhyloP100

-0.55

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over