2-238256995-C-T

Variant names:

• chr2-238256995-C-T
• rs2304670
• NM_022817.3:c.1992G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BA1

The NM_022817.3(PER2):​c.1992G>A​(p.Ala664Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.092 in 1,613,452 control chromosomes in the GnomAD database, including 7,586 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.098 (776 hom., cov: 33)
  • Exomes 𝑓: 0.091 (6810 hom.)
• Consequence: PER2 NM_022817.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.216
• Publications: 17 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=-0.33).
• BP6: Variant 2-238256995-C-T is Benign according to our data. Variant chr2-238256995-C-T is described in ClinVar as Benign. ClinVar VariationId is 3055371.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.216 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.119 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.1992G>A	p.Ala664Ala	synonymous	Exon 17 of 23	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.1992G>A	p.Ala664Ala	synonymous	Exon 17 of 23	ENSP00000254657.3	O15055-1
	PER2	ENST00000707129.1		c.1992G>A	p.Ala664Ala	synonymous	Exon 17 of 23	ENSP00000516757.1	O15055-1
	PER2	ENST00000707130.1		c.1992G>A	p.Ala664Ala	synonymous	Exon 17 of 23	ENSP00000516758.1	O15055-1

Frequencies

GnomAD3 genomes AF: 0.0977 AC: 14860 AN: 152152 Hom.: 776 Cov.: 33

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0590

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.0580

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0906

Gnomad OTH AF: 0.0923

GnomAD2 exomes AF: 0.0974 AC: 24462 AN: 251084 AF XY: 0.102

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.0356

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.0535

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.0944

Gnomad OTH exome AF: 0.0958

GnomAD4 exome AF: 0.0914 AC: 133524 AN: 1461182 Hom.: 6810 Cov.: 32 AF XY: 0.0940 AC XY: 68339 AN XY: 726928

African (AFR) AF: 0.106 AC: 3532 AN: 33474

American (AMR) AF: 0.0382 AC: 1709 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3258 AN: 26132

East Asian (EAS) AF: 0.0585 AC: 2322 AN: 39700

South Asian (SAS) AF: 0.140 AC: 12082 AN: 86240

European-Finnish (FIN) AF: 0.163 AC: 8661 AN: 52986

Middle Eastern (MID) AF: 0.139 AC: 801 AN: 5764

European-Non Finnish (NFE) AF: 0.0857 AC: 95305 AN: 1111784

Other (OTH) AF: 0.0969 AC: 5854 AN: 60382

GnomAD4 genome AF: 0.0976 AC: 14868 AN: 152270 Hom.: 776 Cov.: 33 AF XY: 0.102 AC XY: 7600 AN XY: 74440

African (AFR) AF: 0.104 AC: 4323 AN: 41556

American (AMR) AF: 0.0589 AC: 902 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 450 AN: 3470

East Asian (EAS) AF: 0.0579 AC: 300 AN: 5180

South Asian (SAS) AF: 0.128 AC: 616 AN: 4822

European-Finnish (FIN) AF: 0.171 AC: 1810 AN: 10606

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0906 AC: 6163 AN: 68016

Other (OTH) AF: 0.0909 AC: 192 AN: 2112

Alfa AF: 0.0894 Hom.: 1255

Bravo AF: 0.0889

Asia WGS AF: 0.0760 AC: 264 AN: 3478

EpiCase AF: 0.0893

EpiControl AF: 0.0886

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PER2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	11
DANN	Benign	0.91
PhyloP100		-0.22
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: rs2304670; hg19: chr2-239165636; COSMIC: COSV54521519; COSMIC: COSV54521519;