2-238277281-T-G

Variant names:

• chr2-238277281-T-G
• rs2304673
• NM_022817.3:c.231-88A>C

Variant summary

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

The NM_022817.3(PER2):​c.231-88A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 882,020 control chromosomes in the GnomAD database, including 7,576 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 0.11 (1215 hom., cov: 32)
  • Exomes 𝑓: 0.13 (6361 hom.)
• Consequence: PER2 NM_022817.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.412
• Publications: 21 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.166 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER2	NM_022817.3	MANE Select	c.231-88A>C		intron	N/A	NP_073728.1	O15055-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER2	ENST00000254657.8	TSL:1 MANE Select	c.231-88A>C		intron	N/A	ENSP00000254657.3	O15055-1
	PER2	ENST00000355768.6	TSL:1	n.231-88A>C		intron	N/A
	PER2	ENST00000707129.1		c.231-88A>C		intron	N/A	ENSP00000516757.1	O15055-1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16699 AN: 152118 Hom.: 1215 Cov.: 32

Gnomad AFR AF: 0.0406

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.0870

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.0561

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.118

GnomAD4 exome AF: 0.127 AC: 92511 AN: 729784 Hom.: 6361 AF XY: 0.122 AC XY: 47844 AN XY: 390758

African (AFR) AF: 0.0393 AC: 765 AN: 19464

American (AMR) AF: 0.193 AC: 8380 AN: 43426

Ashkenazi Jewish (ASJ) AF: 0.0939 AC: 2019 AN: 21512

East Asian (EAS) AF: 0.111 AC: 4044 AN: 36442

South Asian (SAS) AF: 0.0528 AC: 3752 AN: 71092

European-Finnish (FIN) AF: 0.160 AC: 8282 AN: 51914

Middle Eastern (MID) AF: 0.0635 AC: 267 AN: 4202

European-Non Finnish (NFE) AF: 0.136 AC: 60650 AN: 445412

Other (OTH) AF: 0.120 AC: 4352 AN: 36320

GnomAD4 genome AF: 0.110 AC: 16705 AN: 152236 Hom.: 1215 Cov.: 32 AF XY: 0.110 AC XY: 8225 AN XY: 74448

African (AFR) AF: 0.0405 AC: 1681 AN: 41556

American (AMR) AF: 0.172 AC: 2622 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0870 AC: 302 AN: 3470

East Asian (EAS) AF: 0.106 AC: 550 AN: 5188

South Asian (SAS) AF: 0.0564 AC: 272 AN: 4826

European-Finnish (FIN) AF: 0.154 AC: 1629 AN: 10604

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9264 AN: 67990

Other (OTH) AF: 0.118 AC: 248 AN: 2110

Alfa AF: 0.127 Hom.: 1902

Bravo AF: 0.109

Asia WGS AF: 0.0720 AC: 248 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.19
DANN	Benign	0.65
PhyloP100		-0.41
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2304673;

hg19: chr2-239185922;

COSMIC: COSV54522224;