chr2-238246445-C-T

Variant names:

Variant summary

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

The NM_022817.3(PER2):c.3698G>A(p.Ser1233Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000957 in 1,609,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S1233S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

PER2
NM_022817.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.928

Publications

1 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:

ENSG00000225057 (HGNC:):

ENSG00000225057 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=0.014330268).

BS2

High AC in GnomAd4 at 9 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022817.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER2	NM_022817.3	MANE Select	c.3698G>A	p.Ser1233Asn	missense	Exon 23 of 23	NP_073728.1	O15055-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PER2	ENST00000254657.8	TSL:1 MANE Select	c.3698G>A	p.Ser1233Asn	missense	Exon 23 of 23	ENSP00000254657.3	O15055-1
PER2	ENST00000707129.1		c.3698G>A	p.Ser1233Asn	missense	Exon 23 of 23	ENSP00000516757.1	O15055-1
PER2	ENST00000707130.1		c.3698G>A	p.Ser1233Asn	missense	Exon 23 of 23	ENSP00000516758.1	O15055-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000196

AC:

AN:

250638

AF XY:

0.000192

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.0000995

AC:

145

AN:

1457270

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

725210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33394

American (AMR)

AF:

0.000448

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00123

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.000383

AC:

AN:

86102

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000451

AC:

AN:

1107918

Other (OTH)

AF:

0.000133

AC:

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41430

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000203

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.040

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.54

M_CAP

Benign

0.0094

MetaRNN

Benign

0.014

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

0.93

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.10

REVEL

Benign

0.10

Sift

Benign

0.76

Sift4G

Benign

1.0

Polyphen

0.46

Vest4

0.064

MutPred

0.16

Loss of phosphorylation at S1233 (P = 0.0302)

MVP

0.44

MPC

0.62

ClinPred

0.035

GERP RS

3.1

Varity_R

0.033

gMVP

0.13

Mutation Taster

=98/2

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over