rs4429421

Positions:

• chr2-238255792-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022817.3(PER2):​c.2185G>A​(p.Val729Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,614,158 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.0037 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (56 hom.)
• Consequence: PER2 NM_022817.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.57

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006024629).
• BP6: Variant 2-238255792-C-T is Benign according to our data. Variant chr2-238255792-C-T is described in ClinVar as [Benign]. Clinvar id is 770136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0037 (564/152288) while in subpopulation AMR AF= 0.0297 (454/15300). AF 95% confidence interval is 0.0274. There are 6 homozygotes in gnomad4. There are 317 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 564 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PER2	NM_022817.3	c.2185G>A	p.Val729Ile	missense_variant	18/23	ENST00000254657.8	NP_073728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PER2	ENST00000254657.8	c.2185G>A	p.Val729Ile	missense_variant	18/23	1	NM_022817.3	ENSP00000254657.3
PER2	ENST00000707129.1	c.2185G>A	p.Val729Ile	missense_variant	18/23			ENSP00000516757.1
PER2	ENST00000707130.1	c.2185G>A	p.Val729Ile	missense_variant	18/23			ENSP00000516758.1

Frequencies

GnomAD3 genomes AF: 0.00367 AC: 559 AN: 152170 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00713

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00695 AC: 1748 AN: 251448 Hom.: 47 AF XY: 0.00531 AC XY: 722 AN XY: 135902

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.0439

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00924

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00537

GnomAD4 exome AF: 0.00155 AC: 2266 AN: 1461870 Hom.: 56 Cov.: 31 AF XY: 0.00129 AC XY: 941 AN XY: 727244

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.0420

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00587

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00370 AC: 564 AN: 152288 Hom.: 6 Cov.: 33 AF XY: 0.00426 AC XY: 317 AN XY: 74466

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.0297

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00715

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000611 Hom.: 1

Bravo AF: 0.00565

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00527 AC: 640

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.094
Sift	Benign	0.036	D
Sift4G	Uncertain	0.040	D
Polyphen		0.60	P
Vest4		0.14
MVP		0.18
MPC		0.19
ClinPred		0.054	T
GERP RS		0.96
Varity_R		0.031
gMVP		0.26

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: rs4429421; hg19: chr2-239164433;