rs2289591

Positions:

• chr17-8144692-C-A
• chr17-8144692-C-G
• chr17-8144692-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002616.3(PER1):​c.2461+59G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,535,698 control chromosomes in the GnomAD database, including 41,028 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 0.16 (2728 hom., cov: 32)
  • Exomes 𝑓: 0.23 (38300 hom.)
• Consequence: PER1 NM_002616.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.679

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004916042).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PER1	NM_002616.3	c.2461+59G>T		intron_variant		ENST00000317276.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PER1	ENST00000317276.9	c.2461+59G>T		intron_variant		1	NM_002616.3	P1

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25104 AN: 152116 Hom.: 2729 Cov.: 32

Gnomad AFR AF: 0.0441

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.0358

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.171

GnomAD3 exomes AF: 0.169 AC: 23486 AN: 138940 Hom.: 2475 AF XY: 0.174 AC XY: 13010 AN XY: 74844

Gnomad AFR exome AF: 0.0385

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.226

Gnomad EAS exome AF: 0.0437

Gnomad SAS exome AF: 0.124

Gnomad FIN exome AF: 0.188

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.209

GnomAD4 exome AF: 0.227 AC: 313445 AN: 1383464 Hom.: 38300 Cov.: 29 AF XY: 0.224 AC XY: 153293 AN XY: 682920

Gnomad4 AFR exome AF: 0.0341

Gnomad4 AMR exome AF: 0.116

Gnomad4 ASJ exome AF: 0.228

Gnomad4 EAS exome AF: 0.0277

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.188

Gnomad4 NFE exome AF: 0.252

Gnomad4 OTH exome AF: 0.203

GnomAD4 genome AF: 0.165 AC: 25098 AN: 152234 Hom.: 2728 Cov.: 32 AF XY: 0.160 AC XY: 11914 AN XY: 74438

Gnomad4 AFR AF: 0.0440

Gnomad4 AMR AF: 0.150

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.0353

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.177

Gnomad4 NFE AF: 0.249

Gnomad4 OTH AF: 0.169

Alfa AF: 0.163 Hom.: 602

Bravo AF: 0.159

TwinsUK AF: 0.264 AC: 980

ALSPAC AF: 0.254 AC: 979

ExAC AF: 0.105 AC: 10226

Asia WGS AF: 0.0700 AC: 241 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.20
DANN	Benign	0.51
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P;P
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.016
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.19	T
Vest4		0.22
MutPred		0.27		Gain of ubiquitination at K829 (P = 0.0418);
ClinPred		0.00078	T
GERP RS		-3.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2289591; hg19: chr17-8048010; COSMIC: COSV57917166; COSMIC: COSV57917166;