rs6431590

Variant names:

• chr2-238256487-A-G
• rs6431590
• NM_022817.3:c.2065+435T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022817.3(PER2):​c.2065+435T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 152,098 control chromosomes in the GnomAD database, including 15,444 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (15444 hom., cov: 33)
• Consequence: PER2 NM_022817.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.926
• Publications: 23 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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PER2	NM_022817.3	c.2065+435T>C		intron_variant	Intron 17 of 22	ENST00000254657.8	NP_073728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PER2	ENST00000254657.8	c.2065+435T>C		intron_variant	Intron 17 of 22	1	NM_022817.3	ENSP00000254657.3
PER2	ENST00000707129.1	c.2065+435T>C		intron_variant	Intron 17 of 22			ENSP00000516757.1
PER2	ENST00000707130.1	c.2065+435T>C		intron_variant	Intron 17 of 22			ENSP00000516758.1

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64506 AN: 151980 Hom.: 15403 Cov.: 33

Gnomad AFR AF: 0.658

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.464

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.395

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.425 AC: 64615 AN: 152098 Hom.: 15444 Cov.: 33 AF XY: 0.429 AC XY: 31869 AN XY: 74352

African (AFR) AF: 0.659 AC: 27327 AN: 41482

American (AMR) AF: 0.346 AC: 5291 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1003 AN: 3470

East Asian (EAS) AF: 0.323 AC: 1673 AN: 5182

South Asian (SAS) AF: 0.394 AC: 1897 AN: 4820

European-Finnish (FIN) AF: 0.464 AC: 4899 AN: 10566

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.313 AC: 21296 AN: 67970

Other (OTH) AF: 0.401 AC: 846 AN: 2112

Alfa AF: 0.349 Hom.: 27915

Bravo AF: 0.422

Asia WGS AF: 0.372 AC: 1291 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.038
DANN	Benign	0.26
PhyloP100		-0.93
Mutation Taster		=100/0	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: rs6431590; hg19: chr2-239165128;