11-45847449-T-C

Variant names:

• chr11-45847449-T-C
• rs754319957
• ENST00000443527.6:c.22T>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000443527.6(CRY2):​c.22T>C​(p.Tyr8His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000763 in 1,442,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: CRY2 ENST00000443527.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.231

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09360707).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRY2	NM_001127457.3	c.32+168T>C		intron_variant	Intron 1 of 11		NP_001120929.1
CRY2	NM_021117.5	c.-42T>C		upstream_gene_variant		ENST00000616080.2	NP_066940.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRY2	ENST00000616080.2	c.-42T>C		upstream_gene_variant		1	NM_021117.5	ENSP00000484684.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000881 AC: 2 AN: 226940 Hom.: 0 AF XY: 0.0000160 AC XY: 2 AN XY: 125088

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000193

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000763 AC: 11 AN: 1442492 Hom.: 0 Cov.: 36 AF XY: 0.00000838 AC XY: 6 AN XY: 716050

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000906

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000832 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.22T>C (p.Y8H) alteration is located in exon 1 (coding exon 1) of the CRY2 gene. This alteration results from a T to C substitution at nucleotide position 22, causing the tyrosine (Y) at amino acid position 8 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.5
DANN	Benign	0.69
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.40	.;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.094	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.27	N;.
REVEL	Benign	0.027
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.24
MutPred		0.41		Gain of disorder (P = 0.0101);Gain of disorder (P = 0.0101);
MVP		0.043
MPC		0.74
ClinPred		0.069	T
GERP RS		-0.85
gMVP		0.55

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: rs754319957; hg19: chr11-45869000;