dbSNP rs72902437: CRY2:c.468-141T>C (chr11-45860707-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_021117.5(CRY2):c.468-141T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 874,956 control chromosomes in the GnomAD database, including 390 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.022 ( 60 hom., cov: 32)

Exomes 𝑓: 0.028 ( 330 hom. )

Consequence

CRY2
NM_021117.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.243

Publications

3 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0224 (3410/152306) while in subpopulation NFE AF = 0.0336 (2284/68020). AF 95% confidence interval is 0.0324. There are 60 homozygotes in GnomAd4. There are 1631 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3410 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRY2	NM_021117.5 link	c.468-141T>C		intron_variant	Intron 3 of 11	ENST00000616080.2	NP_066940.3	Q49AN0-1A0A0D2X7Z3A2I2P1
CRY2	NM_001127457.3 link	c.285-141T>C		intron_variant	Intron 3 of 11		NP_001120929.1	Q49AN0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRY2	ENST00000616080.2 link	c.468-141T>C		intron_variant	Intron 3 of 11	1	NM_021117.5	ENSP00000484684.1		Q49AN0-1

Frequencies

GnomAD3 genomes

AF:

0.0224

AC:

3414

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00533

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.0279

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0322

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0336

Gnomad OTH

AF:

0.0234

GnomAD4 exome

AF:

0.0278

AC:

20068

AN:

722650

Hom.:

330

AF XY:

0.0272

AC XY:

10085

AN XY:

371162

show subpopulations

African (AFR)

AF:

0.00544

AC:

AN:

18212

American (AMR)

AF:

0.0253

AC:

677

AN:

26718

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

261

AN:

15340

East Asian (EAS)

AF:

0.0000563

AC:

AN:

35550

South Asian (SAS)

AF:

0.00371

AC:

186

AN:

50102

European-Finnish (FIN)

AF:

0.0305

AC:

1237

AN:

40554

Middle Eastern (MID)

AF:

0.0178

AC:

AN:

3764

European-Non Finnish (NFE)

AF:

0.0333

AC:

16554

AN:

497738

Other (OTH)

AF:

0.0284

AC:

985

AN:

34672

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

939

1877

2816

3754

4693

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

410

820

1230

1640

2050

<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:

0.0224

AC:

3410

AN:

152306

Hom.:

Cov.:

AF XY:

0.0219

AC XY:

1631

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00532

AC:

221

AN:

41568

American (AMR)

AF:

0.0278

AC:

426

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0322

AC:

342

AN:

10616

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0336

AC:

2284

AN:

68020

Other (OTH)

AF:

0.0232

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

178

356

533

711

889

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0297

Hom.:

Bravo

AF:

0.0212

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

7.3

(source)

DANN

Benign

0.67

PhyloP100

0.24

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

Other links and lift over