12-107001328-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_004075.5(CRY1):c.636T>C(p.Gly212=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 1,611,886 control chromosomes in the GnomAD database, including 349,652 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.70 (38529 hom., cov: 32)
  • Exomes 𝑓: 0.65 (311123 hom.)
• Consequence: CRY1 NM_004075.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.71

Genes affected

CRY1 (HGNC:2384): (cryptochrome circadian regulator 1) 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. Loss of the related gene in mouse results in a shortened circadian cycle in complete darkness. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 12-107001328-A-G is Benign according to our data. Variant chr12-107001328-A-G is described in ClinVar as [Benign]. Clinvar id is 3059240.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.71 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRY1	NM_004075.5	c.636T>C	p.Gly212=	synonymous_variant	5/13	ENST00000008527.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRY1	ENST00000008527.10	c.636T>C	p.Gly212=	synonymous_variant	5/13	1	NM_004075.5	P1
CRY1	ENST00000546722.1	n.129T>C		non_coding_transcript_exon_variant	2/3	3
CRY1	ENST00000552790.5	n.1195T>C		non_coding_transcript_exon_variant	7/13	2

Frequencies

GnomAD3 genomes AF: 0.702 AC: 106744 AN: 152000 Hom.: 38461 Cov.: 32

Gnomad AFR AF: 0.826

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.763

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.968

Gnomad SAS AF: 0.713

Gnomad FIN AF: 0.580

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.622

Gnomad OTH AF: 0.683

GnomAD3 exomes AF: 0.691 AC: 173239 AN: 250782 Hom.: 61605 AF XY: 0.683 AC XY: 92570 AN XY: 135594

Gnomad AFR exome AF: 0.830

Gnomad AMR exome AF: 0.809

Gnomad ASJ exome AF: 0.556

Gnomad EAS exome AF: 0.974

Gnomad SAS exome AF: 0.715

Gnomad FIN exome AF: 0.573

Gnomad NFE exome AF: 0.619

Gnomad OTH exome AF: 0.652

GnomAD4 exome AF: 0.648 AC: 946094 AN: 1459766 Hom.: 311123 Cov.: 41 AF XY: 0.649 AC XY: 470993 AN XY: 726206

Gnomad4 AFR exome AF: 0.834

Gnomad4 AMR exome AF: 0.802

Gnomad4 ASJ exome AF: 0.549

Gnomad4 EAS exome AF: 0.958

Gnomad4 SAS exome AF: 0.714

Gnomad4 FIN exome AF: 0.572

Gnomad4 NFE exome AF: 0.625

Gnomad4 OTH exome AF: 0.669

GnomAD4 genome AF: 0.703 AC: 106880 AN: 152120 Hom.: 38529 Cov.: 32 AF XY: 0.705 AC XY: 52438 AN XY: 74354

Gnomad4 AFR AF: 0.826

Gnomad4 AMR AF: 0.764

Gnomad4 ASJ AF: 0.551

Gnomad4 EAS AF: 0.968

Gnomad4 SAS AF: 0.714

Gnomad4 FIN AF: 0.580

Gnomad4 NFE AF: 0.622

Gnomad4 OTH AF: 0.684

Alfa AF: 0.638 Hom.: 68652

Bravo AF: 0.722

Asia WGS AF: 0.835 AC: 2901 AN: 3476

EpiCase AF: 0.627

EpiControl AF: 0.623

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CRY1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	0.41
Dann	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs8192440; hg19: chr12-107395106;