rs35572922

Positions:

• chr2-238277924-C-A
• chr2-238277924-C-G
• chr2-238277924-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_022817.3(PER2):​c.13G>T​(p.Ala5Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000416 in 1,613,676 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A5G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (2 hom.)
• Consequence: PER2 NM_022817.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.360

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002901882).
• BS2: High AC in GnomAd4 at 294 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PER2	NM_022817.3	c.13G>T	p.Ala5Ser	missense_variant	2/23	ENST00000254657.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PER2	ENST00000254657.8	c.13G>T	p.Ala5Ser	missense_variant	2/23	1	NM_022817.3	P1

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152252 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00656

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: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000696 AC: 172 AN: 247300 Hom.: 1 AF XY: 0.000425 AC XY: 57 AN XY: 133984

Gnomad AFR exome AF: 0.00755

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000258 AC: 377 AN: 1461306 Hom.: 2 Cov.: 33 AF XY: 0.000226 AC XY: 164 AN XY: 726896

Gnomad4 AFR exome AF: 0.00711

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.00193 AC: 294 AN: 152370 Hom.: 2 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74516

Gnomad4 AFR AF: 0.00654

Gnomad4 AMR AF: 0.000914

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.00225

ESP6500AA AF: 0.00885 AC: 39

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000725 AC: 88

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.065
DANN	Benign	0.92
DEOGEN2	Benign	0.039	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.27	N;N
REVEL	Benign	0.0050
Sift	Benign	0.22	T;D
Sift4G	Benign	0.45	T;.
Polyphen		0.090	B;.
Vest4		0.024
MVP		0.32
MPC		0.35
ClinPred		0.011	T
GERP RS		-0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.049

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35572922; hg19: chr2-239186565; COSMIC: COSV99612868;