17-8143586-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002616.3(PER1):c.2752A>G(p.Met918Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,464,482 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: PER1 NM_002616.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.457

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014360607).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PER1	NM_002616.3	c.2752A>G	p.Met918Val	missense_variant	19/23	ENST00000317276.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PER1	ENST00000317276.9	c.2752A>G	p.Met918Val	missense_variant	19/23	1	NM_002616.3	P1
PER1	ENST00000581082.5	c.2683A>G	p.Met895Val	missense_variant	18/22	5
PER1	ENST00000578089.1	n.685A>G		non_coding_transcript_exon_variant	4/4	3
PER1	ENST00000582719.5	c.2462-751A>G		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 18 AN: 151182 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000629

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.0000738

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000160 AC: 15 AN: 93642 Hom.: 0 AF XY: 0.000213 AC XY: 10 AN XY: 46910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.000466

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000426

Gnomad FIN exome AF: 0.0000894

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000386

GnomAD4 exome AF: 0.000121 AC: 159 AN: 1313184 Hom.: 1 Cov.: 34 AF XY: 0.000122 AC XY: 78 AN XY: 637502

Gnomad4 AFR exome AF: 0.000103

Gnomad4 AMR exome AF: 0.000214

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000574

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.0000435

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.0000922

GnomAD4 genome AF: 0.000119 AC: 18 AN: 151298 Hom.: 0 Cov.: 29 AF XY: 0.000149 AC XY: 11 AN XY: 73920

Gnomad4 AFR AF: 0.000146

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000630

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000738

Gnomad4 OTH AF: 0.000476

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.000136

ExAC AF: 0.0000622 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2022

The c.2752A>G (p.M918V) alteration is located in exon 19 (coding exon 18) of the PER1 gene. This alteration results from a A to G substitution at nucleotide position 2752, causing the methionine (M) at amino acid position 918 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	7.8
Dann	Benign	0.33
DEOGEN2	Benign	0.096	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.89	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.15	N;.
REVEL	Benign	0.21
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.19
MVP		0.082
MPC		0.13
ClinPred		0.014	T
GERP RS		0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs754330323; hg19: chr17-8046904; COSMIC: COSV57918873; COSMIC: COSV57918873;