chr15-90602327-G-C

Variant names:

• chr15-90602327-G-C
• NM_022769.5:c.355G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_022769.5(CRTC3):​c.355G>C​(p.Asp119His) variant causes a missense change. The variant allele was found at a frequency of 0.000000703 in 1,422,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 7.0e-7 (0 hom.)
• Consequence: CRTC3 NM_022769.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.48

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC3	NM_022769.5	c.355G>C	p.Asp119His	missense_variant	Exon 4 of 15	ENST00000268184.11	NP_073606.3
CRTC3	NM_001042574.3	c.355G>C	p.Asp119His	missense_variant	Exon 4 of 15		NP_001036039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTC3	ENST00000268184.11	c.355G>C	p.Asp119His	missense_variant	Exon 4 of 15	1	NM_022769.5	ENSP00000268184.6
CRTC3	ENST00000420329.6	c.355G>C	p.Asp119His	missense_variant	Exon 4 of 15	2		ENSP00000416573.2
CRTC3	ENST00000558005.1	c.46G>C	p.Asp16His	missense_variant	Exon 2 of 7	4		ENSP00000452676.1
CRTC3	ENST00000686240.1	n.355G>C		non_coding_transcript_exon_variant	Exon 4 of 14			ENSP00000508866.1
CRTC3	ENST00000687075.1	n.178G>C		non_coding_transcript_exon_variant	Exon 3 of 9			ENSP00000510590.1
CRTC3	ENST00000691029.1	n.355G>C		non_coding_transcript_exon_variant	Exon 4 of 17			ENSP00000510507.1
CRTC3	ENST00000692149.1	n.355G>C		non_coding_transcript_exon_variant	Exon 4 of 13			ENSP00000510448.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422660 Hom.: 0 Cov.: 25 AF XY: 0.00000141 AC XY: 1 AN XY: 710078

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	.;D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.98	D;D
Vest4		0.89
MutPred		0.34		Gain of MoRF binding (P = 0.045);Gain of MoRF binding (P = 0.045);
MVP		0.52
MPC		0.26
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.52
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: chr15-91145559;