rs2304672

Variant names:

• chr2-238277948-G-C
• rs2304672
• NM_022817.3:c.-12C>G

Variant summary

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

The NM_022817.3(PER2):​c.-12C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.087 in 1,611,976 control chromosomes in the GnomAD database, including 6,907 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.093 (710 hom., cov: 33)
  • Exomes 𝑓: 0.086 (6197 hom.)
• Consequence: PER2 NM_022817.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.246
• Publications: 69 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PER2	NM_022817.3	c.-12C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 23	ENST00000254657.8	NP_073728.1
PER2	NM_022817.3	c.-12C>G		5_prime_UTR_variant	Exon 2 of 23	ENST00000254657.8	NP_073728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PER2	ENST00000254657.8	c.-12C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 23	1	NM_022817.3	ENSP00000254657.3
PER2	ENST00000254657.8	c.-12C>G		5_prime_UTR_variant	Exon 2 of 23	1	NM_022817.3	ENSP00000254657.3

Frequencies

GnomAD3 genomes AF: 0.0926 AC: 14092 AN: 152172 Hom.: 709 Cov.: 33

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0477

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.0575

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0852

Gnomad OTH AF: 0.0846

GnomAD2 exomes AF: 0.0938 AC: 22785 AN: 242956 AF XY: 0.0982

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.0329

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.0545

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.0893

Gnomad OTH exome AF: 0.0927

GnomAD4 exome AF: 0.0864 AC: 126151 AN: 1459686 Hom.: 6197 Cov.: 33 AF XY: 0.0892 AC XY: 64729 AN XY: 726008

African (AFR) AF: 0.103 AC: 3430 AN: 33444

American (AMR) AF: 0.0345 AC: 1536 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2875 AN: 26102

East Asian (EAS) AF: 0.0591 AC: 2344 AN: 39682

South Asian (SAS) AF: 0.139 AC: 11995 AN: 86052

European-Finnish (FIN) AF: 0.163 AC: 8632 AN: 53022

Middle Eastern (MID) AF: 0.142 AC: 732 AN: 5156

European-Non Finnish (NFE) AF: 0.0802 AC: 89083 AN: 1111436

Other (OTH) AF: 0.0917 AC: 5524 AN: 60272

GnomAD4 genome AF: 0.0926 AC: 14096 AN: 152290 Hom.: 710 Cov.: 33 AF XY: 0.0969 AC XY: 7215 AN XY: 74460

African (AFR) AF: 0.100 AC: 4166 AN: 41548

American (AMR) AF: 0.0477 AC: 730 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 405 AN: 3472

East Asian (EAS) AF: 0.0575 AC: 298 AN: 5186

South Asian (SAS) AF: 0.127 AC: 612 AN: 4828

European-Finnish (FIN) AF: 0.170 AC: 1800 AN: 10592

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0852 AC: 5798 AN: 68036

Other (OTH) AF: 0.0833 AC: 176 AN: 2114

Alfa AF: 0.0970 Hom.: 150

Bravo AF: 0.0826

Asia WGS AF: 0.0760 AC: 264 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	9.2
DANN	Benign	0.61
PhyloP100		0.25
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2304672; hg19: chr2-239186589;