2-238251643-A-G

Variant names:

• chr2-238251643-A-G
• NM_022817.3:c.3230T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022817.3(PER2):​c.3230T>C​(p.Leu1077Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PER2 NM_022817.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.07

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]

ENSG00000225057 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PER2	NM_022817.3	c.3230T>C	p.Leu1077Pro	missense_variant	Exon 20 of 23	ENST00000254657.8	NP_073728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PER2	ENST00000254657.8	c.3230T>C	p.Leu1077Pro	missense_variant	Exon 20 of 23	1	NM_022817.3	ENSP00000254657.3
PER2	ENST00000707129.1	c.3230T>C	p.Leu1077Pro	missense_variant	Exon 20 of 23			ENSP00000516757.1
PER2	ENST00000707130.1	c.3230T>C	p.Leu1077Pro	missense_variant	Exon 20 of 23			ENSP00000516758.1
ENSG00000225057	ENST00000456601.1	n.1525-2545A>G		intron_variant	Intron 5 of 6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3230T>C (p.L1077P) alteration is located in exon 20 (coding exon 19) of the PER2 gene. This alteration results from a T to C substitution at nucleotide position 3230, causing the leucine (L) at amino acid position 1077 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	2.9	M
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.28
Sift	Benign	0.22	T
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.23		Gain of relative solvent accessibility (P = 0.0023);
MVP		0.45
MPC		1.1
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.61
gMVP		0.37

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: chr2-239160284;