dbSNP rs3747548: CRY2:p.Ala12Glu (chr11-45847462-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 13/18 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.62

Publications

4 publications found

Variant links:

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]

CRY2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
CRY2	NM_001127457.3 link	c.32+181C>A		intron_variant	Intron 1 of 11		NP_001120929.1	Q49AN0-2
CRY2	NM_021117.5 link	c.-29C>A		upstream_gene_variant		ENST00000616080.2	NP_066940.3	Q49AN0-1A0A0D2X7Z3A2I2P1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRY2	ENST00000616080.2 link	c.-29C>A		upstream_gene_variant		1	NM_021117.5	ENSP00000484684.1		Q49AN0-1

Frequencies

GnomAD3 genomes

AF:

0.00710

AC:

1081

AN:

152206

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0106

AC:

2387

AN:

225630

AF XY:

0.00850

show subpopulations

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 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.:

Cov.:

AF XY:

0.00255

AC XY:

1826

AN XY:

717016

show subpopulations

African (AFR)

AF:

0.000963

AC:

AN:

33214

American (AMR)

AF:

0.0533

AC:

2328

AN:

43660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25616

East Asian (EAS)

AF:

0.0287

AC:

1133

AN:

39428

South Asian (SAS)

AF:

0.00228

AC:

194

AN:

85156

European-Finnish (FIN)

AF:

0.0000432

AC:

AN:

46304

Middle Eastern (MID)

AF:

0.000185

AC:

AN:

5400

European-Non Finnish (NFE)

AF:

0.0000887

AC:

AN:

1105454

Other (OTH)

AF:

0.00355

AC:

212

AN:

59684

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

245

490

736

981

1226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00714

AC:

1088

AN:

152326

Hom.:

Cov.:

AF XY:

0.00904

AC XY:

673

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41586

American (AMR)

AF:

0.0562

AC:

860

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0234

AC:

121

AN:

5180

South Asian (SAS)

AF:

0.00415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68022

Other (OTH)

AF:

0.00614

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00237

Hom.:

Bravo

AF:

0.00948

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00122

AC:

ESP6500EA

AF:

0.000241

AC:

ExAC

AF:

0.00738

AC:

886

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 16, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.91

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.33

.;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-1.1

PhyloP100

1.6

PrimateAI

Uncertain

0.68

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

GERP RS

2.9

PromoterAI

0.0045

Neutral

(source)

gMVP

0.41

Mutation Taster

=87/13

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over