chr12-106997376-T-A

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1709 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRY1	NM_004075.5	c.1503A>T	p.Ala501Ala	synonymous_variant	Exon 10 of 13	ENST00000008527.10	NP_004066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRY1	ENST00000008527.10	c.1503A>T	p.Ala501Ala	synonymous_variant	Exon 10 of 13	1	NM_004075.5	ENSP00000008527.5
CRY1	ENST00000549356.1	c.63A>T	p.Ala21Ala	synonymous_variant	Exon 2 of 4	3		ENSP00000447738.1
CRY1	ENST00000552790.5	n.2082A>T		non_coding_transcript_exon_variant	Exon 12 of 13	2

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

GnomAD3 exomes AF: 0.00292 AC: 732 AN: 251062 Hom.: 12 AF XY: 0.00223 AC XY: 303 AN XY: 135736

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0364

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000737

Gnomad4 OTH exome AF: 0.00255

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

Gnomad4 AFR AF: 0.0388

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00473

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 21, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CRY1-related disorder Benign:1

Mar 21, 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.8
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs112678362; hg19: chr12-107391154;