rs4964518

Variant names:

• chr12-107072439-C-T
• rs4964518
• NM_004075.5:c.158+20365G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004075.5(CRY1):​c.158+20365G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 152,012 control chromosomes in the GnomAD database, including 6,024 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 0.20 (6024 hom., cov: 32)
• Consequence: CRY1 NM_004075.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.242
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRY1	NM_004075.5	c.158+20365G>A		intron_variant	Intron 1 of 12	ENST00000008527.10	NP_004066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRY1	ENST00000008527.10	c.158+20365G>A		intron_variant	Intron 1 of 12	1	NM_004075.5	ENSP00000008527.5

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30754 AN: 151894 Hom.: 6014 Cov.: 32

Gnomad AFR AF: 0.502

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.0741

Gnomad EAS AF: 0.245

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.0699

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0586

Gnomad OTH AF: 0.169

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.203 AC: 30815 AN: 152012 Hom.: 6024 Cov.: 32 AF XY: 0.201 AC XY: 14955 AN XY: 74280

African (AFR) AF: 0.502 AC: 20807 AN: 41426

American (AMR) AF: 0.176 AC: 2681 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0741 AC: 257 AN: 3468

East Asian (EAS) AF: 0.245 AC: 1262 AN: 5156

South Asian (SAS) AF: 0.137 AC: 660 AN: 4818

European-Finnish (FIN) AF: 0.0699 AC: 740 AN: 10580

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0586 AC: 3983 AN: 67982

Other (OTH) AF: 0.170 AC: 359 AN: 2114

Alfa AF: 0.114 Hom.: 3970

Bravo AF: 0.224

Asia WGS AF: 0.232 AC: 806 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.56
DANN	Benign	0.44
PhyloP100		-0.24
Mutation Taster		=100/0	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: rs4964518; hg19: chr12-107466217;