chr2-238246412-C-T

Position:

• chr2-238246412-C-T

Variant summary

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

The ENST00000254657.8(PER2):​c.3731G>A​(p.Gly1244Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,610,074 control chromosomes in the GnomAD database, including 33,535 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (2413 hom., cov: 32)
  • Exomes 𝑓: 0.20 (31122 hom.)
• Consequence: PER2 ENST00000254657.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00341174).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PER2	NM_022817.3	c.3731G>A	p.Gly1244Glu	missense_variant	23/23	ENST00000254657.8	NP_073728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PER2	ENST00000254657.8	c.3731G>A	p.Gly1244Glu	missense_variant	23/23	1	NM_022817.3	ENSP00000254657	P1
	ENST00000456601.1	n.1165C>T		non_coding_transcript_exon_variant	4/7	2
PER2	ENST00000707129.1	c.3731G>A	p.Gly1244Glu	missense_variant	23/23			ENSP00000516757	P1
PER2	ENST00000707130.1	c.3731G>A	p.Gly1244Glu	missense_variant	23/23			ENSP00000516758	P1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23420 AN: 152024 Hom.: 2407 Cov.: 32

Gnomad AFR AF: 0.0379

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.189

GnomAD3 exomes AF: 0.206 AC: 51188 AN: 247886 Hom.: 6186 AF XY: 0.203 AC XY: 27205 AN XY: 134190

Gnomad AFR exome AF: 0.0338

Gnomad AMR exome AF: 0.364

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.279

Gnomad SAS exome AF: 0.204

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.194

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.199 AC: 290708 AN: 1457934 Hom.: 31122 Cov.: 31 AF XY: 0.199 AC XY: 144376 AN XY: 725186

Gnomad4 AFR exome AF: 0.0332

Gnomad4 AMR exome AF: 0.354

Gnomad4 ASJ exome AF: 0.153

Gnomad4 EAS exome AF: 0.297

Gnomad4 SAS exome AF: 0.206

Gnomad4 FIN exome AF: 0.121

Gnomad4 NFE exome AF: 0.199

Gnomad4 OTH exome AF: 0.188

GnomAD4 genome AF: 0.154 AC: 23425 AN: 152140 Hom.: 2413 Cov.: 32 AF XY: 0.154 AC XY: 11419 AN XY: 74386

Gnomad4 AFR AF: 0.0378

Gnomad4 AMR AF: 0.257

Gnomad4 ASJ AF: 0.149

Gnomad4 EAS AF: 0.268

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.113

Gnomad4 NFE AF: 0.195

Gnomad4 OTH AF: 0.187

Alfa AF: 0.192 Hom.: 7174

Bravo AF: 0.162

TwinsUK AF: 0.199 AC: 738

ALSPAC AF: 0.191 AC: 738

ESP6500AA AF: 0.0443 AC: 195

ESP6500EA AF: 0.190 AC: 1633

ExAC AF: 0.198 AC: 24072

Asia WGS AF: 0.214 AC: 745 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.6
DANN	Benign	0.79
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.099
Sift	Benign	0.94	T
Sift4G	Benign	1.0	T
Polyphen		0.020	B
Vest4		0.050
MPC		0.30
ClinPred		0.0028	T
GERP RS		2.9
Varity_R		0.035
gMVP		0.35

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: rs934945; hg19: chr2-239155053; COSMIC: COSV54522780;