11-45847550-C-G

Variant names:

• chr11-45847550-C-G
• NM_021117.5:c.60C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021117.5(CRY2):​c.60C>G​(p.Asp20Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CRY2 NM_021117.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.84

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

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=0.04172924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRY2	NM_021117.5	c.60C>G	p.Asp20Glu	missense_variant	Exon 1 of 12	ENST00000616080.2	NP_066940.3
CRY2	NM_001127457.3	c.32+269C>G		intron_variant	Intron 1 of 11		NP_001120929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRY2	ENST00000616080.2	c.60C>G	p.Asp20Glu	missense_variant	Exon 1 of 12	1	NM_021117.5	ENSP00000484684.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.123C>G (p.D41E) alteration is located in exon 1 (coding exon 1) of the CRY2 gene. This alteration results from a C to G substitution at nucleotide position 123, causing the aspartic acid (D) at amino acid position 41 to be replaced by a glutamic acid (E). 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	0.088
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.039
DANN	Benign	0.77
DEOGEN2	Benign	0.032	.;.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0088	N
LIST_S2	Benign	0.34	.;T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;.;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.52	N;.;.
REVEL	Benign	0.029
Sift	Benign	0.99	T;.;.
Sift4G	Benign	1.0	T;T;T
Vest4		0.096
MutPred		0.26		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);.;
MVP		0.20
MPC		0.53
ClinPred		0.13	T
GERP RS		-9.8
Varity_R		0.044
gMVP		0.24

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: chr11-45869101;