dbSNP rs776050157: CRY2:p.Ala14Glu (chr11-45847531-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_021117.5(CRY2):c.41C>A(p.Ala14Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000768 in 1,431,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A14V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

CRY2
NM_021117.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.339

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03588116).

BS2

High AC in GnomAdExome4 at 11 AD gene.

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.41C>A	p.Ala14Glu	missense	Exon 1 of 12	NP_066940.3	A2I2P1
	CRY2	NM_001127457.3		c.32+250C>A		intron	N/A	NP_001120929.1	Q49AN0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRY2	ENST00000616080.2	TSL:1 MANE Select	c.41C>A	p.Ala14Glu	missense	Exon 1 of 12	ENSP00000484684.1	Q49AN0-1
CRY2	ENST00000443527.6	TSL:1	c.104C>A	p.Ala35Glu	missense	Exon 1 of 12	ENSP00000406751.2	A0A0D2X7Z3
CRY2	ENST00000616623.4	TSL:1	c.104C>A	p.Ala35Glu	missense	Exon 1 of 12	ENSP00000478187.1	A0A0D2X7Z3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000535

AC:

AN:

187018

AF XY:

0.0000386

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000312

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000683

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000768

AC:

AN:

1431606

Hom.:

Cov.:

AF XY:

0.00000704

AC XY:

AN XY:

710336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33210

American (AMR)

AF:

0.000272

AC:

AN:

40426

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25504

East Asian (EAS)

AF:

0.00

AC:

AN:

38882

South Asian (SAS)

AF:

0.00

AC:

AN:

83446

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43028

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101964

Other (OTH)

AF:

0.00

AC:

AN:

59470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.000396

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000344

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.44

CADD

Benign

6.3

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.059

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.37

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.036

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

-0.34

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.19

REVEL

Benign

0.0080

Sift

Benign

0.69

Sift4G

Benign

0.71

Vest4

0.21

MutPred

0.32

Gain of solvent accessibility (P = 0.0068)

MVP

0.082

MPC

0.67

ClinPred

0.053

GERP RS

0.77

PromoterAI

0.041

Neutral

(source)

Varity_R

0.039

gMVP

0.46

Mutation Taster

=86/14

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over