2-238253316-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 27 publications found

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]

PER2 Gene-Disease associations (from GenCC):

• advanced sleep phase syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• advanced sleep phase syndrome 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000225057 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4578 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022817.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER2	NM_022817.3	MANE Select	c.2707G>A	p.Val903Ile	missense	Exon 19 of 23	NP_073728.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER2	ENST00000254657.8	TSL:1 MANE Select	c.2707G>A	p.Val903Ile	missense	Exon 19 of 23	ENSP00000254657.3
	PER2	ENST00000707129.1		c.2707G>A	p.Val903Ile	missense	Exon 19 of 23	ENSP00000516757.1
	PER2	ENST00000707130.1		c.2707G>A	p.Val903Ile	missense	Exon 19 of 23	ENSP00000516758.1

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

GnomAD2 exomes AF: 0.0293 AC: 7344 AN: 250722 AF XY: 0.0291

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 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

African (AFR) AF: 0.00762 AC: 255 AN: 33472

American (AMR) AF: 0.0237 AC: 1061 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0386 AC: 1007 AN: 26102

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39682

South Asian (SAS) AF: 0.00465 AC: 401 AN: 86176

European-Finnish (FIN) AF: 0.0355 AC: 1896 AN: 53366

Middle Eastern (MID) AF: 0.0161 AC: 93 AN: 5760

European-Non Finnish (NFE) AF: 0.0435 AC: 48367 AN: 1111664

Other (OTH) AF: 0.0349 AC: 2106 AN: 60366

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

African (AFR) AF: 0.00883 AC: 367 AN: 41552

American (AMR) AF: 0.0312 AC: 478 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 137 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4826

European-Finnish (FIN) AF: 0.0370 AC: 392 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0456 AC: 3100 AN: 68016

Other (OTH) AF: 0.0341 AC: 72 AN: 2110

Alfa AF: 0.0379 Hom.: 283

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 v4.9

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
PhyloP100		0.35
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
Mutation Taster		=95/5	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: rs35333999; hg19: chr2-239161957;