chr2-238252989-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022817.3(PER2):​c.3034G>C​(p.Ala1012Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A1012T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

PER2
NM_022817.3 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.20
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0416874).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PER2NM_022817.3 linkc.3034G>C p.Ala1012Pro missense_variant Exon 19 of 23 ENST00000254657.8 NP_073728.1 O15055-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PER2ENST00000254657.8 linkc.3034G>C p.Ala1012Pro missense_variant Exon 19 of 23 1 NM_022817.3 ENSP00000254657.3 O15055-1
PER2ENST00000707129.1 linkc.3034G>C p.Ala1012Pro missense_variant Exon 19 of 23 ENSP00000516757.1 O15055-1
PER2ENST00000707130.1 linkc.3034G>C p.Ala1012Pro missense_variant Exon 19 of 23 ENSP00000516758.1 O15055-1
ENSG00000225057ENST00000456601.1 linkn.1525-1199C>G intron_variant Intron 5 of 6 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461660
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
727120
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.79
CADD
Benign
0.080
DANN
Benign
0.94
DEOGEN2
Benign
0.049
T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.091
N
LIST_S2
Benign
0.41
T
M_CAP
Benign
0.0034
T
MetaRNN
Benign
0.042
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.34
N
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-0.30
N
REVEL
Benign
0.030
Sift
Benign
0.13
T
Sift4G
Benign
0.21
T
Polyphen
0.44
B
Vest4
0.051
MutPred
0.21
Gain of glycosylation at A1012 (P = 0.0371);
MVP
0.12
MPC
0.28
ClinPred
0.24
T
GERP RS
-6.0
Varity_R
0.077
gMVP
0.18

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-239161630; API