rs2304671

Variant names:

• chr2-238256992-C-T
• rs2304671
• NM_022817.3:c.1995G>A
• PER2 p.Ser665Ser

Your query was ambiguous. Multiple possible variants found:

• chr2-238256992-C-T
• chr2-238256992-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_022817.3(PER2):​c.1995G>A​(p.Ser665Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0564 in 1,613,494 control chromosomes in the GnomAD database, including 3,098 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (311 hom., cov: 33)
  • Exomes 𝑓: 0.056 (2787 hom.)
• Consequence: PER2 NM_022817.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.676
• Publications: 11 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 2-238256992-C-T is Benign according to our data. Variant chr2-238256992-C-T is described in ClinVar as Benign. ClinVar VariationId is 1278506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.676 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.118 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.1995G>A	p.Ser665Ser	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.1995G>A	p.Ser665Ser	synonymous	Exon 17 of 23	ENSP00000254657.3	O15055-1
	PER2	ENST00000707129.1		c.1995G>A	p.Ser665Ser	synonymous	Exon 17 of 23	ENSP00000516757.1	O15055-1
	PER2	ENST00000707130.1		c.1995G>A	p.Ser665Ser	synonymous	Exon 17 of 23	ENSP00000516758.1	O15055-1

Frequencies

GnomAD3 genomes AF: 0.0594 AC: 9034 AN: 152158 Hom.: 312 Cov.: 33

Gnomad AFR AF: 0.0627

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0370

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0985

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0504

Gnomad OTH AF: 0.0483

GnomAD2 exomes AF: 0.0607 AC: 15231 AN: 250958 AF XY: 0.0639

Gnomad AFR exome AF: 0.0658

Gnomad AMR exome AF: 0.0211

Gnomad ASJ exome AF: 0.0241

Gnomad EAS exome AF: 0.107

Gnomad FIN exome AF: 0.0864

Gnomad NFE exome AF: 0.0490

Gnomad OTH exome AF: 0.0531

GnomAD4 exome AF: 0.0561 AC: 81957 AN: 1461218 Hom.: 2787 Cov.: 31 AF XY: 0.0578 AC XY: 42051 AN XY: 726942

African (AFR) AF: 0.0644 AC: 2156 AN: 33474

American (AMR) AF: 0.0238 AC: 1063 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 693 AN: 26134

East Asian (EAS) AF: 0.113 AC: 4489 AN: 39700

South Asian (SAS) AF: 0.113 AC: 9751 AN: 86242

European-Finnish (FIN) AF: 0.0861 AC: 4559 AN: 52958

Middle Eastern (MID) AF: 0.0609 AC: 351 AN: 5766

European-Non Finnish (NFE) AF: 0.0498 AC: 55415 AN: 1111844

Other (OTH) AF: 0.0576 AC: 3480 AN: 60384

GnomAD4 genome AF: 0.0593 AC: 9030 AN: 152276 Hom.: 311 Cov.: 33 AF XY: 0.0626 AC XY: 4662 AN XY: 74444

African (AFR) AF: 0.0626 AC: 2602 AN: 41568

American (AMR) AF: 0.0369 AC: 565 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 96 AN: 3468

East Asian (EAS) AF: 0.106 AC: 551 AN: 5182

South Asian (SAS) AF: 0.126 AC: 606 AN: 4814

European-Finnish (FIN) AF: 0.0985 AC: 1045 AN: 10612

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0504 AC: 3430 AN: 68000

Other (OTH) AF: 0.0473 AC: 100 AN: 2114

Alfa AF: 0.0432 Hom.: 83

Bravo AF: 0.0531

Asia WGS AF: 0.103 AC: 359 AN: 3478

EpiCase AF: 0.0490

EpiControl AF: 0.0491

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	7.7
DANN	Benign	0.92
PhyloP100		0.68
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: rs2304671;

hg19: chr2-239165633;

COSMIC: COSV54524016;

COSMIC: COSV54524016;