12-106992962-T-G

Variant names:

• chr12-106992962-T-G
• rs184039278
• NM_004075.5:c.1657+3A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_004075.5(CRY1):​c.1657+3A>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00438 in 1,614,074 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as association,risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.0037 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (36 hom.)
• Consequence: CRY1 NM_004075.5 splice_region, intron
• Scores: Splicing: ADA: 0.9984
• Clinical Significance: association; risk factor no assertion criteria provided O:2
• Conservation: PhyloP100: 4.18
• Publications: 14 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: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS2: High AC in GnomAd4 at 569 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRY1	NM_004075.5	c.1657+3A>C		splice_region_variant, intron_variant	Intron 11 of 12	ENST00000008527.10	NP_004066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRY1	ENST00000008527.10	c.1657+3A>C		splice_region_variant, intron_variant	Intron 11 of 12	1	NM_004075.5	ENSP00000008527.5
CRY1	ENST00000552790.5	n.2239A>C		non_coding_transcript_exon_variant	Exon 13 of 13	2
CRY1	ENST00000549356.1	c.217+3A>C		splice_region_variant, intron_variant	Intron 3 of 3	3		ENSP00000447738.1

Frequencies

GnomAD3 genomes AF: 0.00375 AC: 570 AN: 152200 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.0374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00456

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00461 AC: 1158 AN: 251380 AF XY: 0.00470

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00413

Gnomad ASJ exome AF: 0.0332

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00495

Gnomad OTH exome AF: 0.00636

GnomAD4 exome AF: 0.00445 AC: 6502 AN: 1461756 Hom.: 36 Cov.: 31 AF XY: 0.00457 AC XY: 3321 AN XY: 727174

African (AFR) AF: 0.000717 AC: 24 AN: 33478

American (AMR) AF: 0.00425 AC: 190 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 804 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00185 AC: 160 AN: 86254

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53414

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5768

European-Non Finnish (NFE) AF: 0.00437 AC: 4854 AN: 1111912

Other (OTH) AF: 0.00646 AC: 390 AN: 60392

GnomAD4 genome AF: 0.00374 AC: 569 AN: 152318 Hom.: 5 Cov.: 32 AF XY: 0.00388 AC XY: 289 AN XY: 74488

African (AFR) AF: 0.000553 AC: 23 AN: 41568

American (AMR) AF: 0.00568 AC: 87 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0374 AC: 130 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00456 AC: 310 AN: 68020

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00517 Hom.: 4

Bravo AF: 0.00419

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00562

EpiControl AF: 0.00616

ClinVar

Significance: association; risk factor

Submissions summary: Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Delayed sleep phase syndrome, susceptibility to Other:1

May 25, 2017

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Sleep-wake schedule disorder, delayed phase type;C1263846:Attention deficit hyperactivity disorder Other:1

Jul 01, 2020

Yale Center for Mendelian Genomics, Yale University

Significance: association

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Benign	16
DANN	Uncertain	0.98
PhyloP100		4.2
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs184039278; hg19: chr12-107386740;