2-238253316-C-T

Variant names:

• chr2-238253316-C-T
• rs35333999
• NM_022817.3:c.2707G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_022817.3(PER2):​c.2707G>A​(p.Val903Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.037 in 1,613,532 control chromosomes in the GnomAD database, including 1,215 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.030 (80 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1135 hom.)
• Consequence: PER2 NM_022817.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.349

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027523339).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0301 (4578/152270) while in subpopulation NFE AF= 0.0456 (3100/68016). AF 95% confidence interval is 0.0442. There are 80 homozygotes in gnomad4. There are 2232 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4578 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PER2	NM_022817.3	c.2707G>A	p.Val903Ile	missense_variant	Exon 19 of 23	ENST00000254657.8	NP_073728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PER2	ENST00000254657.8	c.2707G>A	p.Val903Ile	missense_variant	Exon 19 of 23	1	NM_022817.3	ENSP00000254657.3
PER2	ENST00000707129.1	c.2707G>A	p.Val903Ile	missense_variant	Exon 19 of 23			ENSP00000516757.1
PER2	ENST00000707130.1	c.2707G>A	p.Val903Ile	missense_variant	Exon 19 of 23			ENSP00000516758.1
ENSG00000225057	ENST00000456601.1	n.1525-872C>T		intron_variant	Intron 5 of 6	2

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4583 AN: 152152 Hom.: 81 Cov.: 33

Gnomad AFR AF: 0.00886

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0314

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0370

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0456

Gnomad OTH AF: 0.0345

GnomAD3 exomes AF: 0.0293 AC: 7344 AN: 250722 Hom.: 139 AF XY: 0.0291 AC XY: 3941 AN XY: 135610

Gnomad AFR exome AF: 0.00839

Gnomad AMR exome AF: 0.0228

Gnomad ASJ exome AF: 0.0378

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00403

Gnomad FIN exome AF: 0.0354

Gnomad NFE exome AF: 0.0436

Gnomad OTH exome AF: 0.0347

GnomAD4 exome AF: 0.0378 AC: 55188 AN: 1461262 Hom.: 1135 Cov.: 34 AF XY: 0.0371 AC XY: 26955 AN XY: 726842

Gnomad4 AFR exome AF: 0.00762

Gnomad4 AMR exome AF: 0.0237

Gnomad4 ASJ exome AF: 0.0386

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00465

Gnomad4 FIN exome AF: 0.0355

Gnomad4 NFE exome AF: 0.0435

Gnomad4 OTH exome AF: 0.0349

GnomAD4 genome AF: 0.0301 AC: 4578 AN: 152270 Hom.: 80 Cov.: 33 AF XY: 0.0300 AC XY: 2232 AN XY: 74460

Gnomad4 AFR AF: 0.00883

Gnomad4 AMR AF: 0.0312

Gnomad4 ASJ AF: 0.0395

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0370

Gnomad4 NFE AF: 0.0456

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.0397 Hom.: 213

Bravo AF: 0.0287

TwinsUK AF: 0.0369 AC: 137

ALSPAC AF: 0.0426 AC: 164

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0456 AC: 392

ExAC AF: 0.0291 AC: 3530

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0399

EpiControl AF: 0.0411

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.055
Sift	Benign	0.16	T
Sift4G	Benign	0.49	T
Polyphen		0.98	D
Vest4		0.064
MPC		0.38
ClinPred		0.011	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.11

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: rs35333999; hg19: chr2-239161957;