12-106991676-T-G

Variant names:

• chr12-106991676-T-G
• rs8192441
• NM_004075.5:c.*326A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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 -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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1590 AD gene.

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.*326A>C		3_prime_UTR	Exon 13 of 13	NP_004066.1
	CRY1	NR_182152.1		n.2605A>C		non_coding_transcript_exon	Exon 13 of 13
	CRY1	NR_182153.1		n.2241A>C		non_coding_transcript_exon	Exon 12 of 12

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRY1	ENST00000008527.10	TSL:1 MANE Select	c.*326A>C		3_prime_UTR	Exon 13 of 13	ENSP00000008527.5
	CRY1	ENST00000552790.5	TSL:2	n.3525A>C		non_coding_transcript_exon	Exon 13 of 13

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0141 AC: 6 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 4

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

African (AFR) AF: 0.00322 AC: 134 AN: 41578

American (AMR) AF: 0.00634 AC: 97 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4834

European-Finnish (FIN) AF: 0.00923 AC: 98 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0174 AC: 1180 AN: 67990

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	7.8
DANN	Benign	0.87
PhyloP100		0.77
Mutation Taster		=100/0	polymorphism

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: rs8192441; hg19: chr12-107385454;