chr11-45867677-C-T

Variant names:

• chr11-45867677-C-T
• rs35488012
• NM_021117.5:c.807C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_021117.5(CRY2):​c.807C>T​(p.Gly269Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,614,258 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (40 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (31 hom.)
• Consequence: CRY2 NM_021117.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.897
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 11-45867677-C-T is Benign according to our data. Variant chr11-45867677-C-T is described in ClinVar as Benign. ClinVar VariationId is 780966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.897 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0114 (1743/152368) while in subpopulation AFR AF = 0.0402 (1671/41580). AF 95% confidence interval is 0.0386. There are 40 homozygotes in GnomAd4. There are 838 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1743 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRY2	NM_021117.5	MANE Select	c.807C>T	p.Gly269Gly	synonymous	Exon 6 of 12	NP_066940.3
	CRY2	NM_001127457.3		c.624C>T	p.Gly208Gly	synonymous	Exon 6 of 12	NP_001120929.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRY2	ENST00000616080.2	TSL:1 MANE Select	c.807C>T	p.Gly269Gly	synonymous	Exon 6 of 12	ENSP00000484684.1
	CRY2	ENST00000443527.6	TSL:1	c.870C>T	p.Gly290Gly	synonymous	Exon 6 of 12	ENSP00000406751.2
	CRY2	ENST00000616623.4	TSL:1	c.870C>T	p.Gly290Gly	synonymous	Exon 6 of 12	ENSP00000478187.1

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1744 AN: 152250 Hom.: 41 Cov.: 33

Gnomad AFR AF: 0.0403

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00313 AC: 786 AN: 251474 AF XY: 0.00238

Gnomad AFR exome AF: 0.0423

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00114 AC: 1660 AN: 1461890 Hom.: 31 Cov.: 30 AF XY: 0.000993 AC XY: 722 AN XY: 727246

African (AFR) AF: 0.0401 AC: 1344 AN: 33480

American (AMR) AF: 0.00241 AC: 108 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1112010

Other (OTH) AF: 0.00278 AC: 168 AN: 60396

GnomAD4 genome AF: 0.0114 AC: 1743 AN: 152368 Hom.: 40 Cov.: 33 AF XY: 0.0112 AC XY: 838 AN XY: 74516

African (AFR) AF: 0.0402 AC: 1671 AN: 41580

American (AMR) AF: 0.00366 AC: 56 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68040

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00503 Hom.: 7

Bravo AF: 0.0127

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

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 13, 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
BayesDel_noAF	Benign	-0.26
CADD	Benign	14
DANN	Benign	0.65
PhyloP100		0.90
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs35488012; hg19: chr11-45889228;