chr12-107001328-A-G

Variant names:

• chr12-107001328-A-G
• rs8192440
• NM_004075.5:c.636T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_004075.5(CRY1):​c.636T>C​(p.Gly212Gly) 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.70 (38529 hom., cov: 32)
  • Exomes 𝑓: 0.65 (311123 hom.)
• Consequence: CRY1 NM_004075.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.71
• Publications: 49 publications found

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

Our verdict: Benign. The variant received -14 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 VariationId is 3059240.Status of the report is no_assertion_criteria_provided, 0 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004075.5. 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
	CRY1	NM_004075.5	MANE Select	c.636T>C	p.Gly212Gly	synonymous	Exon 5 of 13	NP_004066.1
	CRY1	NM_001413458.1		c.636T>C	p.Gly212Gly	synonymous	Exon 5 of 13	NP_001400387.1
	CRY1	NM_001413459.1		c.636T>C	p.Gly212Gly	synonymous	Exon 5 of 13	NP_001400388.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRY1	ENST00000008527.10	TSL:1 MANE Select	c.636T>C	p.Gly212Gly	synonymous	Exon 5 of 13	ENSP00000008527.5
	CRY1	ENST00000546722.1	TSL:3	n.129T>C		non_coding_transcript_exon	Exon 2 of 3
	CRY1	ENST00000552790.5	TSL:2	n.1195T>C		non_coding_transcript_exon	Exon 7 of 13

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

GnomAD2 exomes AF: 0.691 AC: 173239 AN: 250782 AF XY: 0.683

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 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

African (AFR) AF: 0.834 AC: 27897 AN: 33446

American (AMR) AF: 0.802 AC: 35827 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 14332 AN: 26112

East Asian (EAS) AF: 0.958 AC: 37997 AN: 39666

South Asian (SAS) AF: 0.714 AC: 61397 AN: 86036

European-Finnish (FIN) AF: 0.572 AC: 30527 AN: 53350

Middle Eastern (MID) AF: 0.677 AC: 3901 AN: 5760

European-Non Finnish (NFE) AF: 0.625 AC: 693884 AN: 1110416

Other (OTH) AF: 0.669 AC: 40332 AN: 60324

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

African (AFR) AF: 0.826 AC: 34305 AN: 41510

American (AMR) AF: 0.764 AC: 11673 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 1911 AN: 3468

East Asian (EAS) AF: 0.968 AC: 5022 AN: 5188

South Asian (SAS) AF: 0.714 AC: 3440 AN: 4820

European-Finnish (FIN) AF: 0.580 AC: 6124 AN: 10562

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.622 AC: 42302 AN: 67968

Other (OTH) AF: 0.684 AC: 1444 AN: 2110

Alfa AF: 0.651 Hom.: 150443

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: no assertion criteria provided

Submissions by phenotype

CRY1-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.41
DANN	Benign	0.64
PhyloP100		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8192440; hg19: chr12-107395106; COSMIC: COSV108004887; COSMIC: COSV108004887;