dbSNP rs121908635: PER2:p.Ser662Gly (chr2-238257003-T-C) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_022817.3(PER2):c.1984A>G(p.Ser662Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PER2
NM_022817.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.69

Publications

92 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: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a mutagenesis_site Restores CSNK1E-dependent phosphorylation of variant G-662. (size 0) in uniprot entity PER2_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.851

PP5

Variant 2-238257003-T-C is Pathogenic according to our data. Variant chr2-238257003-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 6345.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PER2	NM_022817.3 link	c.1984A>G	p.Ser662Gly	missense_variant	Exon 17 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.1984A>G	p.Ser662Gly	missense_variant	Exon 17 of 23	1	NM_022817.3	ENSP00000254657.3	O15055-1
PER2	ENST00000707129.1 link	c.1984A>G	p.Ser662Gly	missense_variant	Exon 17 of 23			ENSP00000516757.1	O15055-1
PER2	ENST00000707130.1 link	c.1984A>G	p.Ser662Gly	missense_variant	Exon 17 of 23			ENSP00000516758.1	O15055-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461404

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727044

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53056

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111910

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Advanced sleep phase syndrome 1

Pathogenic:1

Feb 09, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-0.39

MutationAssessor

Pathogenic

3.3

PhyloP100

5.7

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.55

MutPred

0.78

Gain of catalytic residue at S662 (P = 0.013);

MVP

0.57

MPC

0.21

ClinPred

0.99

GERP RS

4.8

Varity_R

0.74

gMVP

0.55

Mutation Taster

=22/78

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs121908635

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over