2-238253162-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_022817.3(PER2):c.2861C>T(p.Ser954Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000501 in 1,595,930 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000053 ( 1 hom. )

Consequence

PER2
NM_022817.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.11

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039121777).

BS2

High AC in GnomAdExome at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PER2	NM_022817.3 linkuse as main transcript	c.2861C>T	p.Ser954Leu	missense_variant	19/23	ENST00000254657.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PER2	ENST00000254657.8 linkuse as main transcript	c.2861C>T	p.Ser954Leu	missense_variant	19/23	1	NM_022817.3	P1	O15055-1
	ENST00000456601.1 linkuse as main transcript	n.1525-1026G>A		intron_variant, non_coding_transcript_variant		2
PER2	ENST00000707129.1 linkuse as main transcript	c.2861C>T	p.Ser954Leu	missense_variant	19/23			P1
PER2	ENST00000707130.1 linkuse as main transcript	c.2861C>T	p.Ser954Leu	missense_variant	19/23			P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000744

AC:

AN:

242082

Hom.:

AF XY:

0.000107

AC XY:

AN XY:

130362

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000365

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000533

AC:

AN:

1443614

Hom.:

Cov.:

AF XY:

0.0000713

AC XY:

AN XY:

714866

show subpopulations

Gnomad4 AFR exome

AF:

0.0000604

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000569

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000200

Gnomad4 OTH exome

AF:

0.0000840

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000577

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The c.2861C>T (p.S954L) alteration is located in exon 19 (coding exon 18) of the PER2 gene. This alteration results from a C to T substitution at nucleotide position 2861, causing the serine (S) at amino acid position 954 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.56

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.52

M_CAP

Benign

0.0057

MetaRNN

Benign

0.039

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.2

REVEL

Benign

0.057

Sift

Benign

0.12

Sift4G

Benign

0.36

Polyphen

0.67

Vest4

0.085

MutPred

0.27

Loss of phosphorylation at S954 (P = 0.0047);

MVP

0.12

MPC

0.51

ClinPred

0.074

GERP RS

3.3

Varity_R

0.041

gMVP

0.14

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over