rs138750527

Positions:

• chr2-238251623-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_022817.3(PER2):​c.3250T>C​(p.Cys1084Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000488 in 1,614,180 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (2 hom.)
• Consequence: PER2 NM_022817.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.28

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]

ENSG00000225057 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047379434).
• BP6: Variant 2-238251623-A-G is Benign according to our data. Variant chr2-238251623-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 376949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-238251623-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 357 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PER2	NM_022817.3	c.3250T>C	p.Cys1084Arg	missense_variant	20/23	ENST00000254657.8	NP_073728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PER2	ENST00000254657.8	c.3250T>C	p.Cys1084Arg	missense_variant	20/23	1	NM_022817.3	ENSP00000254657.3
PER2	ENST00000707129.1	c.3250T>C	p.Cys1084Arg	missense_variant	20/23			ENSP00000516757.1
PER2	ENST00000707130.1	c.3250T>C	p.Cys1084Arg	missense_variant	20/23			ENSP00000516758.1
ENSG00000225057	ENST00000456601.1	n.1525-2565A>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 355 AN: 152184 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00811

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000712 AC: 179 AN: 251292 Hom.: 0 AF XY: 0.000537 AC XY: 73 AN XY: 135886

Gnomad AFR exome AF: 0.00942

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000294 AC: 430 AN: 1461878 Hom.: 2 Cov.: 33 AF XY: 0.000257 AC XY: 187 AN XY: 727242

Gnomad4 AFR exome AF: 0.00983

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.00234 AC: 357 AN: 152302 Hom.: 2 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74478

Gnomad4 AFR AF: 0.00813

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000449 Hom.: 0

Bravo AF: 0.00289

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000791 AC: 96

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 09, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.65
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Benign	0.22
Sift	Benign	0.054	T
Sift4G	Uncertain	0.021	D
Polyphen		0.99	D
Vest4		0.40
MVP		0.24
MPC		1.1
ClinPred		0.10	T
GERP RS		1.7
Varity_R		0.25
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs138750527; hg19: chr2-239160264; COSMIC: COSV99612633;