rs2292913

Variant names:

• chr11-45855978-A-G
• rs2292913
• NM_021117.5:c.216-4A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-45855978-A-G
• chr11-45855978-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021117.5(CRY2):​c.216-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.915 in 1,612,230 control chromosomes in the GnomAD database, including 681,846 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.89 (60920 hom., cov: 32)
  • Exomes 𝑓: 0.92 (620926 hom.)
• Consequence: CRY2 NM_021117.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001303
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.602
• Publications: 16 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.934 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRY2	NM_021117.5	c.216-4A>G		splice_region_variant, intron_variant	Intron 1 of 11	ENST00000616080.2	NP_066940.3
CRY2	NM_001127457.3	c.33-4A>G		splice_region_variant, 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.216-4A>G		splice_region_variant, intron_variant	Intron 1 of 11	1	NM_021117.5	ENSP00000484684.1

Frequencies

GnomAD3 genomes AF: 0.889 AC: 135303 AN: 152124 Hom.: 60877 Cov.: 32

Gnomad AFR AF: 0.841

Gnomad AMI AF: 0.979

Gnomad AMR AF: 0.894

Gnomad ASJ AF: 0.936

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.861

Gnomad FIN AF: 0.950

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.940

Gnomad OTH AF: 0.884

GnomAD2 exomes AF: 0.879 AC: 220974 AN: 251412 AF XY: 0.882

Gnomad AFR exome AF: 0.841

Gnomad AMR exome AF: 0.871

Gnomad ASJ exome AF: 0.936

Gnomad EAS exome AF: 0.463

Gnomad FIN exome AF: 0.948

Gnomad NFE exome AF: 0.936

Gnomad OTH exome AF: 0.901

GnomAD4 exome AF: 0.918 AC: 1340403 AN: 1459988 Hom.: 620926 Cov.: 32 AF XY: 0.917 AC XY: 666065 AN XY: 726420

African (AFR) AF: 0.840 AC: 28086 AN: 33436

American (AMR) AF: 0.874 AC: 39074 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.937 AC: 24490 AN: 26126

East Asian (EAS) AF: 0.430 AC: 17051 AN: 39680

South Asian (SAS) AF: 0.874 AC: 75372 AN: 86222

European-Finnish (FIN) AF: 0.946 AC: 50545 AN: 53404

Middle Eastern (MID) AF: 0.875 AC: 5042 AN: 5764

European-Non Finnish (NFE) AF: 0.942 AC: 1046073 AN: 1110328

Other (OTH) AF: 0.906 AC: 54670 AN: 60322

GnomAD4 genome AF: 0.889 AC: 135403 AN: 152242 Hom.: 60920 Cov.: 32 AF XY: 0.887 AC XY: 66010 AN XY: 74442

African (AFR) AF: 0.841 AC: 34917 AN: 41530

American (AMR) AF: 0.894 AC: 13671 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.936 AC: 3251 AN: 3472

East Asian (EAS) AF: 0.458 AC: 2367 AN: 5166

South Asian (SAS) AF: 0.860 AC: 4152 AN: 4828

European-Finnish (FIN) AF: 0.950 AC: 10079 AN: 10614

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.940 AC: 63946 AN: 68026

Other (OTH) AF: 0.884 AC: 1867 AN: 2112

Alfa AF: 0.917 Hom.: 262878

Bravo AF: 0.880

Asia WGS AF: 0.760 AC: 2646 AN: 3478

EpiCase AF: 0.939

EpiControl AF: 0.935

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	11
DANN	Benign	0.54
PhyloP100		-0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.012
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

Other links and lift over

dbSNP: rs2292913; hg19: chr11-45877529; COSMIC: COSV69888578; COSMIC: COSV69888578;