rs112678362

Variant names:

• chr12-106997376-T-A
• rs112678362
• NM_004075.5:c.1503A>T

Your query was ambiguous. Multiple possible variants found:

• chr12-106997376-T-A
• chr12-106997376-T-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004075.5(CRY1):​c.1503A>T​(p.Ala501Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,613,890 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (24 hom.)
• Consequence: CRY1 NM_004075.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.152
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 12-106997376-T-A is Benign according to our data. Variant chr12-106997376-T-A is described in ClinVar as Benign. ClinVar VariationId is 781261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.152 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0112 (1709/152310) while in subpopulation AFR AF = 0.0388 (1611/41560). AF 95% confidence interval is 0.0372. There are 44 homozygotes in GnomAd4. There are 818 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1709 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRY1	NM_004075.5	MANE Select	c.1503A>T	p.Ala501Ala	synonymous	Exon 10 of 13	NP_004066.1	A2I2P0
	CRY1	NM_001413458.1		c.1503A>T	p.Ala501Ala	synonymous	Exon 10 of 13	NP_001400387.1
	CRY1	NM_001413459.1		c.1503A>T	p.Ala501Ala	synonymous	Exon 10 of 13	NP_001400388.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRY1	ENST00000008527.10	TSL:1 MANE Select	c.1503A>T	p.Ala501Ala	synonymous	Exon 10 of 13	ENSP00000008527.5	Q16526
	CRY1	ENST00000864076.1		c.1503A>T	p.Ala501Ala	synonymous	Exon 10 of 13	ENSP00000534135.1
	CRY1	ENST00000864077.1		c.1503A>T	p.Ala501Ala	synonymous	Exon 10 of 13	ENSP00000534136.1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1687 AN: 152192 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00292 AC: 732 AN: 251062 AF XY: 0.00223

Gnomad AFR exome AF: 0.0378

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00109 AC: 1598 AN: 1461580 Hom.: 24 Cov.: 31 AF XY: 0.000975 AC XY: 709 AN XY: 727070

African (AFR) AF: 0.0364 AC: 1219 AN: 33472

American (AMR) AF: 0.00264 AC: 118 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5766

European-Non Finnish (NFE) AF: 0.0000737 AC: 82 AN: 1111888

Other (OTH) AF: 0.00255 AC: 154 AN: 60384

GnomAD4 genome AF: 0.0112 AC: 1709 AN: 152310 Hom.: 44 Cov.: 32 AF XY: 0.0110 AC XY: 818 AN XY: 74484

African (AFR) AF: 0.0388 AC: 1611 AN: 41560

American (AMR) AF: 0.00510 AC: 78 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68022

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00366 Hom.: 6

Bravo AF: 0.0128

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CRY1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.8
DANN	Benign	0.63
PhyloP100		-0.15
PromoterAI		-0.0024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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: rs112678362; hg19: chr12-107391154;