rs2735611

Variant names:

• chr17-8144965-G-A
• rs2735611
• NM_002616.3:c.2247C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002616.3(PER1):​c.2247C>T​(p.Gly749Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 1,502,102 control chromosomes in the GnomAD database, including 495,548 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 0.71 (40429 hom., cov: 31)
  • Exomes 𝑓: 0.81 (455119 hom.)
• Consequence: PER1 NM_002616.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.386
• Publications: 40 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]

MIR6883 (HGNC:50019): (microRNA 6883) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP7: Synonymous conserved (PhyloP=0.386 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.838 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.2247C>T	p.Gly749Gly	synonymous	Exon 18 of 23	NP_002607.2
	MIR6883	NR_106943.1		n.*29C>T		downstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER1	ENST00000317276.9	TSL:1 MANE Select	c.2247C>T	p.Gly749Gly	synonymous	Exon 18 of 23	ENSP00000314420.4
	PER1	ENST00000581082.6	TSL:5	c.2187C>T	p.Gly729Gly	synonymous	Exon 17 of 22	ENSP00000462064.1
	PER1	ENST00000354903.9	TSL:2	c.2199C>T	p.Gly733Gly	synonymous	Exon 18 of 18	ENSP00000346979.5

Frequencies

GnomAD3 genomes AF: 0.712 AC: 108213 AN: 151892 Hom.: 40429 Cov.: 31

Gnomad AFR AF: 0.561

Gnomad AMI AF: 0.825

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.598

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.763

Gnomad FIN AF: 0.862

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.844

Gnomad OTH AF: 0.696

GnomAD2 exomes AF: 0.710 AC: 116576 AN: 164202 AF XY: 0.729

Gnomad AFR exome AF: 0.544

Gnomad AMR exome AF: 0.438

Gnomad ASJ exome AF: 0.598

Gnomad EAS exome AF: 0.293

Gnomad FIN exome AF: 0.861

Gnomad NFE exome AF: 0.845

Gnomad OTH exome AF: 0.741

GnomAD4 exome AF: 0.812 AC: 1095729 AN: 1350092 Hom.: 455119 Cov.: 32 AF XY: 0.812 AC XY: 536805 AN XY: 661350

African (AFR) AF: 0.548 AC: 16289 AN: 29740

American (AMR) AF: 0.460 AC: 13140 AN: 28596

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 11947 AN: 19686

East Asian (EAS) AF: 0.292 AC: 10996 AN: 37652

South Asian (SAS) AF: 0.770 AC: 52828 AN: 68586

European-Finnish (FIN) AF: 0.870 AC: 41818 AN: 48060

Middle Eastern (MID) AF: 0.671 AC: 2561 AN: 3818

European-Non Finnish (NFE) AF: 0.854 AC: 903700 AN: 1058430

Other (OTH) AF: 0.765 AC: 42450 AN: 55524

GnomAD4 genome AF: 0.712 AC: 108248 AN: 152010 Hom.: 40429 Cov.: 31 AF XY: 0.710 AC XY: 52730 AN XY: 74308

African (AFR) AF: 0.561 AC: 23226 AN: 41426

American (AMR) AF: 0.577 AC: 8805 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.598 AC: 2076 AN: 3470

East Asian (EAS) AF: 0.304 AC: 1569 AN: 5158

South Asian (SAS) AF: 0.765 AC: 3687 AN: 4820

European-Finnish (FIN) AF: 0.862 AC: 9136 AN: 10604

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.844 AC: 57364 AN: 67948

Other (OTH) AF: 0.687 AC: 1450 AN: 2110

Alfa AF: 0.776 Hom.: 60258

Bravo AF: 0.679

Asia WGS AF: 0.533 AC: 1855 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.8
DANN	Benign	0.76
PhyloP100		0.39
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: rs2735611; hg19: chr17-8048283; COSMIC: COSV57920755; COSMIC: COSV57920755;