15-90604395-C-G

Position:

• chr15-90604395-C-G

Variant summary

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

The NM_022769.5(CRTC3):​c.424C>G​(p.Pro142Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CRTC3 NM_022769.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

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]

ENSG00000259314 (HGNC:):

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=0.10495362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRTC3	NM_022769.5	c.424C>G	p.Pro142Ala	missense_variant	5/15	ENST00000268184.11	NP_073606.3
CRTC3	NM_001042574.3	c.424C>G	p.Pro142Ala	missense_variant	5/15		NP_001036039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRTC3	ENST00000268184.11	c.424C>G	p.Pro142Ala	missense_variant	5/15	1	NM_022769.5	ENSP00000268184.6
CRTC3	ENST00000420329.6	c.424C>G	p.Pro142Ala	missense_variant	5/15	2		ENSP00000416573.2
CRTC3	ENST00000558005.1	c.115C>G	p.Pro39Ala	missense_variant	3/7	4		ENSP00000452676.1
CRTC3	ENST00000686240.1	n.424C>G		non_coding_transcript_exon_variant	5/14			ENSP00000508866.1
CRTC3	ENST00000687075.1	n.247C>G		non_coding_transcript_exon_variant	4/9			ENSP00000510590.1
CRTC3	ENST00000691029.1	n.424C>G		non_coding_transcript_exon_variant	5/17			ENSP00000510507.1
CRTC3	ENST00000692149.1	n.424C>G		non_coding_transcript_exon_variant	5/13			ENSP00000510448.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251478 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135914

Gnomad AFR exome AF: 0.0000615

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461670 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 727140

Gnomad4 AFR exome AF: 0.0000299

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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

Aug 27, 2024

The c.424C>G (p.P142A) alteration is located in exon 5 (coding exon 5) of the CRTC3 gene. This alteration results from a C to G substitution at nucleotide position 424, causing the proline (P) at amino acid position 142 to be replaced by an alanine (A). 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	0.057
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Benign	0.12	.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.0049
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.049
Sift	Benign	0.077	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.082	B;B
Vest4		0.34
MutPred		0.20		Loss of catalytic residue at P141 (P = 0.0131);Loss of catalytic residue at P141 (P = 0.0131);
MVP		0.068
MPC		0.047
ClinPred		0.17	T
GERP RS		4.2
Varity_R		0.047
gMVP		0.21

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: rs770320914; hg19: chr15-91147627;