rs8192441

Positions:

• chr12-106991676-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4 BS1 BS2

The NM_004075.5(CRY1):​c.*326A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 152,716 control chromosomes in the GnomAD database, including 12 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 0.010 (12 hom., cov: 33)
  • Exomes 𝑓: 0.014 (0 hom.)
• Consequence: CRY1 NM_004075.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.772

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.17).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0104 (1590/152284) while in subpopulation NFE AF= 0.0174 (1180/67990). AF 95% confidence interval is 0.0165. There are 12 homozygotes in gnomad4. There are 736 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1590 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRY1	NM_004075.5	c.*326A>C		3_prime_UTR_variant	13/13	ENST00000008527.10	NP_004066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRY1	ENST00000008527.10	c.*326A>C		3_prime_UTR_variant	13/13	1	NM_004075.5	ENSP00000008527	P1
CRY1	ENST00000552790.5	n.3525A>C		non_coding_transcript_exon_variant	13/13	2

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1591 AN: 152166 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00323

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00923

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0174

Gnomad OTH AF: 0.00718

GnomAD4 exome AF: 0.0139 AC: 6 AN: 432 Hom.: 0 Cov.: 0 AF XY: 0.00769 AC XY: 2 AN XY: 260

Gnomad4 FIN exome AF: 0.0141

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0104 AC: 1590 AN: 152284 Hom.: 12 Cov.: 33 AF XY: 0.00988 AC XY: 736 AN XY: 74472

Gnomad4 AFR AF: 0.00322

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.00923

Gnomad4 NFE AF: 0.0174

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.0112 Hom.: 3

Bravo AF: 0.0104

Asia WGS AF: 0.00260 AC: 9 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	7.8
DANN	Benign	0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs8192441; hg19: chr12-107385454;