chr15-90540072-A-C

Position:

• chr15-90540072-A-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.166A>C​(p.Thr56Pro) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CRTC3 NM_022769.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.28

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=0.26116318).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRTC3	NM_022769.5	c.166A>C	p.Thr56Pro	missense_variant	2/15	ENST00000268184.11
CRTC3	NM_001042574.3	c.166A>C	p.Thr56Pro	missense_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRTC3	ENST00000268184.11	c.166A>C	p.Thr56Pro	missense_variant	2/15	1	NM_022769.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2023

The c.166A>C (p.T56P) alteration is located in exon 2 (coding exon 2) of the CRTC3 gene. This alteration results from a A to C substitution at nucleotide position 166, causing the threonine (T) at amino acid position 56 to be replaced by a proline (P). 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	0.32
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	.;.;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.62	T;T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;N
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.074	T;T;T
Polyphen		0.94	P;.;P
Vest4		0.42
MutPred		0.28		Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);
MVP		0.47
MPC		1.7
ClinPred		0.80	D
GERP RS		5.2
Varity_R		0.13
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-91083304;