rs3747548

Positions:

• chr11-45847462-C-A
• chr11-45847462-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000443527.6(CRY2):​c.35C>A​(p.Ala12Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00319 in 1,596,242 control chromosomes in the GnomAD database, including 143 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (47 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (96 hom.)
• Consequence: CRY2 ENST00000443527.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.62

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022559166).
• BP6: Variant 11-45847462-C-A is Benign according to our data. Variant chr11-45847462-C-A is described in ClinVar as [Benign]. Clinvar id is 782294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRY2	NM_001127457.3	c.32+181C>A		intron_variant			NP_001120929.1
CRY2	NM_021117.5			upstream_gene_variant		ENST00000616080.2	NP_066940.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRY2	ENST00000616080.2			upstream_gene_variant		1	NM_021117.5	ENSP00000484684	P2

Frequencies

GnomAD3 genomes AF: 0.00710 AC: 1081 AN: 152206 Hom.: 47 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0558

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0233

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.0106 AC: 2387 AN: 225630 Hom.: 76 AF XY: 0.00850 AC XY: 1058 AN XY: 124540

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.0548

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0243

Gnomad SAS exome AF: 0.00229

Gnomad FIN exome AF: 0.0000676

Gnomad NFE exome AF: 0.000137

Gnomad OTH exome AF: 0.00902

GnomAD4 exome AF: 0.00277 AC: 4000 AN: 1443916 Hom.: 96 Cov.: 36 AF XY: 0.00255 AC XY: 1826 AN XY: 717016

Gnomad4 AFR exome AF: 0.000963

Gnomad4 AMR exome AF: 0.0533

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0287

Gnomad4 SAS exome AF: 0.00228

Gnomad4 FIN exome AF: 0.0000432

Gnomad4 NFE exome AF: 0.0000887

Gnomad4 OTH exome AF: 0.00355

GnomAD4 genome AF: 0.00714 AC: 1088 AN: 152326 Hom.: 47 Cov.: 33 AF XY: 0.00904 AC XY: 673 AN XY: 74488

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.0562

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0234

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00185 Hom.: 6

Bravo AF: 0.00948

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00122 AC: 5

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.00738 AC: 886

Asia WGS AF: 0.0250 AC: 85 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 16, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	16
DANN	Benign	0.91
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.33	.;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.14	N;.
REVEL	Benign	0.034
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.34
MPC		0.67
ClinPred		0.13	T
GERP RS		2.9
gMVP		0.41

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

LitVar

Other links and lift over

dbSNP: rs3747548; hg19: chr11-45869013;