chr11-45847462-C-A

Variant names:

• chr11-45847462-C-A
• rs3747548
• ENST00000443527.6:c.35C>A

Variant summary

Our verdict is Benign. The variant received -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. 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.62
• Publications: 4 publications found

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

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000443527.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRY2	NM_001127457.3		c.32+181C>A		intron	N/A	NP_001120929.1
	CRY2	NM_021117.5	MANE Select	c.-29C>A		upstream_gene	N/A	NP_066940.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRY2	ENST00000443527.6	TSL:1	c.35C>A	p.Ala12Glu	missense	Exon 1 of 12	ENSP00000406751.2
	CRY2	ENST00000616623.4	TSL:1	c.35C>A	p.Ala12Glu	missense	Exon 1 of 12	ENSP00000478187.1
	CRY2	ENST00000417225.6	TSL:2	c.32+181C>A		intron	N/A	ENSP00000397419.2

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

GnomAD2 exomes AF: 0.0106 AC: 2387 AN: 225630 AF XY: 0.00850

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.: 96 Cov.: 36 AF XY: 0.00255 AC XY: 1826 AN XY: 717016

African (AFR) AF: 0.000963 AC: 32 AN: 33214

American (AMR) AF: 0.0533 AC: 2328 AN: 43660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 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: 2 AN: 46304

Middle Eastern (MID) AF: 0.000185 AC: 1 AN: 5400

European-Non Finnish (NFE) AF: 0.0000887 AC: 98 AN: 1105454

Other (OTH) AF: 0.00355 AC: 212 AN: 59684

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

African (AFR) AF: 0.00135 AC: 56 AN: 41586

American (AMR) AF: 0.0562 AC: 860 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0234 AC: 121 AN: 5180

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68022

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00237 Hom.: 13

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
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
MetaSVM	Benign	-1.1	T
PhyloP100		1.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.034
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.34
MPC		0.67
ClinPred		0.13	T
GERP RS		2.9
PromoterAI		0.0045	Neutral
gMVP		0.41
Mutation Taster		=87/13	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3747548; hg19: chr11-45869013;