chr17-8143454-C-G

Variant names:

• chr17-8143454-C-G
• rs2585405
• NM_002616.3:c.2884G>C

Variant summary

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

The NM_002616.3(PER1):​c.2884G>C​(p.Ala962Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.885 in 1,607,814 control chromosomes in the GnomAD database, including 633,196 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.85 (55933 hom., cov: 29)
  • Exomes 𝑓: 0.89 (577263 hom.)
• Consequence: PER1 NM_002616.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.553
• Publications: 57 publications found

Genes affected

PER1 (HGNC:8845): (period circadian regulator 1) 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. Alternative splicing has been observed in this gene; however, these variants have not been fully described. [provided by RefSeq, Jan 2014]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=1.1891894E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.898 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002616.3. 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
	PER1	NM_002616.3	MANE Select	c.2884G>C	p.Ala962Pro	missense	Exon 19 of 23	NP_002607.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER1	ENST00000317276.9	TSL:1 MANE Select	c.2884G>C	p.Ala962Pro	missense	Exon 19 of 23	ENSP00000314420.4
	PER1	ENST00000581082.6	TSL:5	c.2815G>C	p.Ala939Pro	missense	Exon 18 of 22	ENSP00000462064.1
	PER1	ENST00000578089.1	TSL:3	n.817G>C		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.855 AC: 129750 AN: 151820 Hom.: 55898 Cov.: 29

Gnomad AFR AF: 0.803

Gnomad AMI AF: 0.840

Gnomad AMR AF: 0.851

Gnomad ASJ AF: 0.736

Gnomad EAS AF: 0.540

Gnomad SAS AF: 0.882

Gnomad FIN AF: 0.932

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.904

Gnomad OTH AF: 0.825

GnomAD2 exomes AF: 0.850 AC: 207710 AN: 244436 AF XY: 0.855

Gnomad AFR exome AF: 0.794

Gnomad AMR exome AF: 0.836

Gnomad ASJ exome AF: 0.749

Gnomad EAS exome AF: 0.520

Gnomad FIN exome AF: 0.927

Gnomad NFE exome AF: 0.902

Gnomad OTH exome AF: 0.851

GnomAD4 exome AF: 0.888 AC: 1292523 AN: 1455878 Hom.: 577263 Cov.: 48 AF XY: 0.888 AC XY: 642495 AN XY: 723872

African (AFR) AF: 0.797 AC: 26581 AN: 33348

American (AMR) AF: 0.836 AC: 37021 AN: 44264

Ashkenazi Jewish (ASJ) AF: 0.751 AC: 19358 AN: 25784

East Asian (EAS) AF: 0.554 AC: 21867 AN: 39494

South Asian (SAS) AF: 0.882 AC: 75370 AN: 85500

European-Finnish (FIN) AF: 0.932 AC: 49443 AN: 53064

Middle Eastern (MID) AF: 0.787 AC: 4510 AN: 5728

European-Non Finnish (NFE) AF: 0.908 AC: 1006762 AN: 1108560

Other (OTH) AF: 0.858 AC: 51611 AN: 60136

GnomAD4 genome AF: 0.855 AC: 129840 AN: 151936 Hom.: 55933 Cov.: 29 AF XY: 0.855 AC XY: 63504 AN XY: 74276

African (AFR) AF: 0.803 AC: 33268 AN: 41410

American (AMR) AF: 0.850 AC: 12979 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 2554 AN: 3472

East Asian (EAS) AF: 0.540 AC: 2763 AN: 5114

South Asian (SAS) AF: 0.883 AC: 4256 AN: 4820

European-Finnish (FIN) AF: 0.932 AC: 9868 AN: 10584

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.904 AC: 61424 AN: 67956

Other (OTH) AF: 0.822 AC: 1736 AN: 2112

Alfa AF: 0.863 Hom.: 10589

Bravo AF: 0.841

TwinsUK AF: 0.905 AC: 3354

ALSPAC AF: 0.909 AC: 3503

ESP6500AA AF: 0.786 AC: 3460

ESP6500EA AF: 0.897 AC: 7713

ExAC AF: 0.851 AC: 103194

Asia WGS AF: 0.736 AC: 2562 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.9
DANN	Benign	0.58
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.086	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	N
PhyloP100		0.55
PrimateAI	Benign	0.43	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.030
Sift	Benign	0.58	T
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.16
MPC		0.17
ClinPred		0.0024	T
GERP RS		3.2
Varity_R		0.066
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2585405; hg19: chr17-8046772; COSMIC: COSV57917411; COSMIC: COSV57917411;