rs934945

Variant names:

• chr2-238246412-C-T
• rs934945
• NM_022817.3:c.3731G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022817.3(PER2):​c.3731G>A​(p.Gly1244Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,610,074 control chromosomes in the GnomAD database, including 33,535 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (2413 hom., cov: 32)
  • Exomes 𝑓: 0.20 (31122 hom.)
• Consequence: PER2 NM_022817.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33
• Publications: 100 publications found

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)

ENSG00000225057 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00341174).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER2	NM_022817.3	MANE Select	c.3731G>A	p.Gly1244Glu	missense	Exon 23 of 23	NP_073728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER2	ENST00000254657.8	TSL:1 MANE Select	c.3731G>A	p.Gly1244Glu	missense	Exon 23 of 23	ENSP00000254657.3
	PER2	ENST00000707129.1		c.3731G>A	p.Gly1244Glu	missense	Exon 23 of 23	ENSP00000516757.1
	PER2	ENST00000707130.1		c.3731G>A	p.Gly1244Glu	missense	Exon 23 of 23	ENSP00000516758.1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23420 AN: 152024 Hom.: 2407 Cov.: 32

Gnomad AFR AF: 0.0379

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.189

GnomAD2 exomes AF: 0.206 AC: 51188 AN: 247886 AF XY: 0.203

Gnomad AFR exome AF: 0.0338

Gnomad AMR exome AF: 0.364

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.279

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.194

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.199 AC: 290708 AN: 1457934 Hom.: 31122 Cov.: 31 AF XY: 0.199 AC XY: 144376 AN XY: 725186

African (AFR) AF: 0.0332 AC: 1109 AN: 33440

American (AMR) AF: 0.354 AC: 15688 AN: 44334

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 3987 AN: 26040

East Asian (EAS) AF: 0.297 AC: 11771 AN: 39640

South Asian (SAS) AF: 0.206 AC: 17718 AN: 85930

European-Finnish (FIN) AF: 0.121 AC: 6431 AN: 53336

Middle Eastern (MID) AF: 0.259 AC: 1491 AN: 5750

European-Non Finnish (NFE) AF: 0.199 AC: 221214 AN: 1109222

Other (OTH) AF: 0.188 AC: 11299 AN: 60242

GnomAD4 genome AF: 0.154 AC: 23425 AN: 152140 Hom.: 2413 Cov.: 32 AF XY: 0.154 AC XY: 11419 AN XY: 74386

African (AFR) AF: 0.0378 AC: 1569 AN: 41526

American (AMR) AF: 0.257 AC: 3933 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 516 AN: 3472

East Asian (EAS) AF: 0.268 AC: 1388 AN: 5170

South Asian (SAS) AF: 0.198 AC: 953 AN: 4818

European-Finnish (FIN) AF: 0.113 AC: 1197 AN: 10590

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13258 AN: 67972

Other (OTH) AF: 0.187 AC: 395 AN: 2116

Alfa AF: 0.186 Hom.: 9644

Bravo AF: 0.162

TwinsUK AF: 0.199 AC: 738

ALSPAC AF: 0.191 AC: 738

ESP6500AA AF: 0.0443 AC: 195

ESP6500EA AF: 0.190 AC: 1633

ExAC AF: 0.198 AC: 24072

Asia WGS AF: 0.214 AC: 745 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.6
DANN	Benign	0.79
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.3
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.099
Sift	Benign	0.94	T
Sift4G	Benign	1.0	T
Polyphen		0.020	B
Vest4		0.050
MPC		0.30
ClinPred		0.0028	T
GERP RS		2.9
Varity_R		0.035
gMVP		0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs934945; hg19: chr2-239155053; COSMIC: COSV54522780;