Genetic Variant NM_021117.5:c.1195-96A>G (chr11-45869957-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_021117.5(CRY2):c.1195-96A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.914 in 1,516,554 control chromosomes in the GnomAD database, including 640,446 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 0.88 ( 59891 hom., cov: 34)

Exomes 𝑓: 0.92 ( 580555 hom. )

Consequence

CRY2
NM_021117.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.97

Publications

9 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=-0.89).

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 link	c.1195-96A>G		intron_variant	Intron 7 of 11	ENST00000616080.2	NP_066940.3	Q49AN0-1A0A0D2X7Z3A2I2P1
CRY2	NM_001127457.3 link	c.1012-96A>G		intron_variant	Intron 7 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.1195-96A>G		intron_variant	Intron 7 of 11	1	NM_021117.5	ENSP00000484684.1		Q49AN0-1

Frequencies

GnomAD3 genomes

AF:

0.881

AC:

134075

AN:

152168

Hom.:

59852

Cov.:

show subpopulations

Gnomad AFR

AF:

0.811

Gnomad AMI

AF:

0.979

Gnomad AMR

AF:

0.891

Gnomad ASJ

AF:

0.936

Gnomad EAS

AF:

0.458

Gnomad SAS

AF:

0.861

Gnomad FIN

AF:

0.950

Gnomad MID

AF:

0.886

Gnomad NFE

AF:

0.940

Gnomad OTH

AF:

0.882

GnomAD4 exome

AF:

0.918

AC:

1252575

AN:

1364268

Hom.:

580555

Cov.:

AF XY:

0.917

AC XY:

614177

AN XY:

669672

show subpopulations

African (AFR)

AF:

0.806

AC:

24832

AN:

30790

American (AMR)

AF:

0.875

AC:

29641

AN:

33858

Ashkenazi Jewish (ASJ)

AF:

0.937

AC:

19400

AN:

20698

East Asian (EAS)

AF:

0.430

AC:

16738

AN:

38904

South Asian (SAS)

AF:

0.874

AC:

63400

AN:

72526

European-Finnish (FIN)

AF:

0.946

AC:

37750

AN:

39894

Middle Eastern (MID)

AF:

0.883

AC:

3439

AN:

3894

European-Non Finnish (NFE)

AF:

0.943

AC:

1006296

AN:

1067300

Other (OTH)

AF:

0.906

AC:

51079

AN:

56404

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

5255

10509

15764

21018

26273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21272

42544

63816

85088

106360

<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:

0.881

AC:

134171

AN:

152286

Hom.:

59891

Cov.:

AF XY:

0.879

AC XY:

65463

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.811

AC:

33669

AN:

41532

American (AMR)

AF:

0.891

AC:

13646

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.936

AC:

3251

AN:

3472

East Asian (EAS)

AF:

0.457

AC:

2359

AN:

5158

South Asian (SAS)

AF:

0.860

AC:

4150

AN:

4828

European-Finnish (FIN)

AF:

0.950

AC:

10092

AN:

10624

Middle Eastern (MID)

AF:

0.881

AC:

259

AN:

294

European-Non Finnish (NFE)

AF:

0.940

AC:

63987

AN:

68042

Other (OTH)

AF:

0.882

AC:

1865

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

780

1561

2341

3122

3902

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

894

1788

2682

3576

4470

<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:

0.917

Hom.:

78181

Bravo

AF:

0.870

Asia WGS

AF:

0.758

AC:

2640

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

5.1

(source)

DANN

Benign

0.66

PhyloP100

2.0

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over