rs2863712

Variant names:

• chr11-45869638-T-G
• rs2863712
• NM_021117.5:c.1015T>G
• CRY2 p.Trp339Gly

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_021117.5(CRY2):​c.1015T>G​(p.Trp339Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CRY2 NM_021117.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.01
• Publications: 3 publications found

Genes affected

CRY2 (HGNC:2385): (cryptochrome circadian regulator 2) This gene encodes a flavin adenine dinucleotide-binding protein that is a key component of the circadian core oscillator complex, which regulates the circadian clock. 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 have been associated with altered sleep patterns. The encoded protein is widely conserved across plants and animals. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2014]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021117.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRY2	NM_021117.5	MANE Select	c.1015T>G	p.Trp339Gly	missense	Exon 7 of 12	NP_066940.3	A2I2P1
	CRY2	NM_001127457.3		c.832T>G	p.Trp278Gly	missense	Exon 7 of 12	NP_001120929.1	Q49AN0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRY2	ENST00000616080.2	TSL:1 MANE Select	c.1015T>G	p.Trp339Gly	missense	Exon 7 of 12	ENSP00000484684.1	Q49AN0-1
	CRY2	ENST00000443527.6	TSL:1	c.1078T>G	p.Trp360Gly	missense	Exon 7 of 12	ENSP00000406751.2	A0A0D2X7Z3
	CRY2	ENST00000616623.4	TSL:1	c.1078T>G	p.Trp360Gly	missense	Exon 7 of 12	ENSP00000478187.1	A0A0D2X7Z3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	33
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0030	D
Varity_R		0.65
gMVP		0.98
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2863712;

hg19: chr11-45891189;