rs373099993

Variant names:

• chr11-45847536-G-A
• rs373099993
• NM_021117.5:c.46G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-45847536-G-A
• chr11-45847536-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021117.5(CRY2):​c.46G>A​(p.Ala16Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,292 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: CRY2 NM_021117.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.337

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053694427).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRY2	NM_021117.5	c.46G>A	p.Ala16Thr	missense_variant	Exon 1 of 12	ENST00000616080.2	NP_066940.3
CRY2	NM_001127457.3	c.32+255G>A		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.46G>A	p.Ala16Thr	missense_variant	Exon 1 of 12	1	NM_021117.5	ENSP00000484684.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152292 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74406

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ESP6500AA AF: 0.000242 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000856 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Benign	0.91
DEOGEN2	Benign	0.029	.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.42	.;T;T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.054	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	.;.;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.26	N;.;.
REVEL	Benign	0.016
Sift	Benign	0.38	T;.;.
Sift4G	Benign	0.54	T;T;T
Vest4		0.14
MVP		0.14
MPC		0.55
ClinPred		0.036	T
GERP RS		0.78
Varity_R		0.025
gMVP		0.23

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: rs373099993; hg19: chr11-45869087;