chr11-45847501-C-T

Variant names:

• chr11-45847501-C-T
• rs1417104105
• NM_021117.5:c.11C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021117.5(CRY2):​c.11C>T​(p.Thr4Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRY2 NM_021117.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.210

Genes affected

CRY2 (HGNC:2385): (cryptochrome circadian regulator 2) 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. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0961692).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRY2	NM_021117.5	c.11C>T	p.Thr4Ile	missense_variant	Exon 1 of 12	ENST00000616080.2	NP_066940.3
CRY2	NM_001127457.3	c.32+220C>T		intron_variant	Intron 1 of 11		NP_001120929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRY2	ENST00000616080.2	c.11C>T	p.Thr4Ile	missense_variant	Exon 1 of 12	1	NM_021117.5	ENSP00000484684.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000475 AC: 1 AN: 210400 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 116764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000613

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000208 AC: 3 AN: 1443920 Hom.: 0 Cov.: 36 AF XY: 0.00000139 AC XY: 1 AN XY: 717668

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.051	.;.;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.44	.;T;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.096	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;.;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.34	N;.;.
REVEL	Benign	0.060
Sift	Uncertain	0.0080	D;.;.
Sift4G	Uncertain	0.010	D;D;D
Vest4		0.41
MutPred		0.40		Loss of glycosylation at T25 (P = 0.0219);Loss of glycosylation at T25 (P = 0.0219);.;
MVP		0.068
MPC		0.62
ClinPred		0.23	T
GERP RS		2.9
Varity_R		0.077
gMVP		0.18

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: rs1417104105; hg19: chr11-45869052;