15-90625991-C-G

Variant names:

• chr15-90625991-C-G
• rs373321970
• NM_022769.5:c.965C>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.965C>G​(p.Ser322Cys) variant causes a missense, splice region 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. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRTC3 NM_022769.5 missense, splice_region
• Scores: Splicing: ADA: 0.8978
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.57

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)

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=0.26155233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC3	NM_022769.5	c.965C>G	p.Ser322Cys	missense_variant, splice_region_variant	Exon 10 of 15	ENST00000268184.11	NP_073606.3
CRTC3	NM_001042574.3	c.965C>G	p.Ser322Cys	missense_variant, splice_region_variant	Exon 10 of 15		NP_001036039.1
CRTC3-AS1	NR_120372.1	n.510-5838G>C		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTC3	ENST00000268184.11	c.965C>G	p.Ser322Cys	missense_variant, splice_region_variant	Exon 10 of 15	1	NM_022769.5	ENSP00000268184.6
CRTC3	ENST00000420329.6	c.965C>G	p.Ser322Cys	missense_variant, splice_region_variant	Exon 10 of 15	2		ENSP00000416573.2
CRTC3	ENST00000686240.1	n.*378C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 14			ENSP00000508866.1
CRTC3	ENST00000687075.1	n.*201C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 9			ENSP00000510590.1
CRTC3	ENST00000691029.1	n.965C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 10 of 17			ENSP00000510507.1
CRTC3	ENST00000692149.1	n.*292C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 13			ENSP00000510448.1
CRTC3	ENST00000686240.1	n.*378C>G		3_prime_UTR_variant	Exon 9 of 14			ENSP00000508866.1
CRTC3	ENST00000687075.1	n.*201C>G		3_prime_UTR_variant	Exon 8 of 9			ENSP00000510590.1
CRTC3	ENST00000692149.1	n.*292C>G		3_prime_UTR_variant	Exon 8 of 13			ENSP00000510448.1
CRTC3	ENST00000558005.1	c.*51C>G		downstream_gene_variant		4		ENSP00000452676.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	.;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	2.0	M;M
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.12
Sift	Benign	0.048	D;T
Sift4G	Benign	0.089	T;T
Polyphen		1.0	D;D
Vest4		0.36
MutPred		0.40		Loss of phosphorylation at S322 (P = 0.011);Loss of phosphorylation at S322 (P = 0.011);
MVP		0.13
MPC		0.29
ClinPred		0.79	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.12
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Benign	0.62
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: rs373321970; hg19: chr15-91169223;