rs773241141

Variant names:

• chr15-90530122-G-C
• rs773241141
• NM_022769.5:c.51G>C

Variant summary

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

The NM_022769.5(CRTC3):​c.51G>C​(p.Glu17Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000762 in 1,311,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: CRTC3 NM_022769.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.10

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]

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=0.24821979).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC3	NM_022769.5	c.51G>C	p.Glu17Asp	missense_variant	Exon 1 of 15	ENST00000268184.11	NP_073606.3
CRTC3	NM_001042574.3	c.51G>C	p.Glu17Asp	missense_variant	Exon 1 of 15		NP_001036039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTC3	ENST00000268184.11	c.51G>C	p.Glu17Asp	missense_variant	Exon 1 of 15	1	NM_022769.5	ENSP00000268184.6
CRTC3	ENST00000420329.6	c.51G>C	p.Glu17Asp	missense_variant	Exon 1 of 15	2		ENSP00000416573.2
CRTC3	ENST00000686240.1	n.51G>C		non_coding_transcript_exon_variant	Exon 1 of 14			ENSP00000508866.1
CRTC3	ENST00000691029.1	n.51G>C		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000510507.1
CRTC3	ENST00000692149.1	n.51G>C		non_coding_transcript_exon_variant	Exon 1 of 13			ENSP00000510448.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000125 AC: 2 AN: 159376 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 88634

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: 0.0000896

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.62e-7 AC: 1 AN: 1311972 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 650458

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: 0.0000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000170 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.51G>C (p.E17D) alteration is located in exon 1 (coding exon 1) of the CRTC3 gene. This alteration results from a G to C substitution at nucleotide position 51, causing the glutamic acid (E) at amino acid position 17 to be replaced by an aspartic acid (D). 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	Pathogenic	1.0
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	.;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.5	M;.;M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.9	N;D;N
REVEL	Benign	0.29
Sift	Benign	0.036	D;D;D
Sift4G	Uncertain	0.013	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.41
MutPred		0.10		Loss of ubiquitination at K18 (P = 0.0561);Loss of ubiquitination at K18 (P = 0.0561);Loss of ubiquitination at K18 (P = 0.0561);
MVP		0.46
MPC		2.0
ClinPred		0.86	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.47

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: rs773241141; hg19: chr15-91073354;