15-90629519-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_022769.5(CRTC3):ā€‹c.1253A>Gā€‹(p.Tyr418Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000041 ( 0 hom. )

Consequence

CRTC3
NM_022769.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.62
Variant links:
Genes affected
CRTC3 (HGNC:26148): (CREB regulated transcription coactivator 3) This gene is a member of the CREB regulated transcription coactivator gene family. This family regulates CREB-dependent gene transcription in a phosphorylation-independent manner and may be selective for cAMP-responsive genes. The protein encoded by this gene may induce mitochondrial biogenesis and attenuate catecholamine signaling in adipose tissue. A translocation event between this gene and Notch coactivator mastermind-like gene 2, which results in a fusion protein, has been reported in mucoepidermoid carcinomas. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Jul 2012]
CRTC3-AS1 (HGNC:51433): (CRTC3 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.29015613).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CRTC3NM_022769.5 linkuse as main transcriptc.1253A>G p.Tyr418Cys missense_variant 11/15 ENST00000268184.11
CRTC3-AS1NR_120372.1 linkuse as main transcriptn.510-9366T>C intron_variant, non_coding_transcript_variant
CRTC3NM_001042574.3 linkuse as main transcriptc.1253A>G p.Tyr418Cys missense_variant 11/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CRTC3ENST00000268184.11 linkuse as main transcriptc.1253A>G p.Tyr418Cys missense_variant 11/151 NM_022769.5 P3Q6UUV7-1
CRTC3-AS1ENST00000559531.1 linkuse as main transcriptn.511-9366T>C intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251298
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135860
show subpopulations
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:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461746
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727142
show subpopulations
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:
0.00000450
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 27, 2022The c.1253A>G (p.Y418C) alteration is located in exon 11 (coding exon 11) of the CRTC3 gene. This alteration results from a A to G substitution at nucleotide position 1253, causing the tyrosine (Y) at amino acid position 418 to be replaced by a cysteine (C). 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
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.16
.;T
Eigen
Benign
0.0064
Eigen_PC
Benign
-0.11
FATHMM_MKL
Benign
0.35
N
LIST_S2
Benign
0.82
T;T
M_CAP
Benign
0.0039
T
MetaRNN
Benign
0.29
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.4
M;M
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-1.4
N;N
REVEL
Benign
0.084
Sift
Benign
0.19
T;T
Sift4G
Benign
0.18
T;T
Polyphen
0.99
D;D
Vest4
0.49
MutPred
0.28
Gain of catalytic residue at P417 (P = 0.0123);Gain of catalytic residue at P417 (P = 0.0123);
MVP
0.15
MPC
0.063
ClinPred
0.34
T
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.064
gMVP
0.36

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs776314268; hg19: chr15-91172751; API