rs193921108

Positions:

• chr15-90638566-C-A
• chr15-90638566-C-G
• chr15-90638566-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022769.5(CRTC3):​c.1387C>A​(p.Arg463Ser) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CRTC3 NM_022769.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.713

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044348627).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRTC3	NM_022769.5	c.1387C>A	p.Arg463Ser	missense_variant	12/15	ENST00000268184.11	NP_073606.3
CRTC3-AS1	NR_120372.1	n.509+2476G>T		intron_variant, non_coding_transcript_variant
CRTC3	NM_001042574.3	c.1387C>A	p.Arg463Ser	missense_variant	12/15		NP_001036039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRTC3	ENST00000268184.11	c.1387C>A	p.Arg463Ser	missense_variant	12/15	1	NM_022769.5	ENSP00000268184	P3
CRTC3-AS1	ENST00000559531.1	n.510+2476G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.4
DANN	Benign	0.87
DEOGEN2	Benign	0.067	.;T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.044	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.11	N;N
REVEL	Benign	0.033
Sift	Benign	0.94	T;T
Sift4G	Benign	0.86	T;T
Polyphen		0.039	B;B
Vest4		0.25
MutPred		0.22		Gain of glycosylation at R463 (P = 0.0127);Gain of glycosylation at R463 (P = 0.0127);
MVP		0.11
MPC		0.055
ClinPred		0.14	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.29

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: rs193921108; hg19: chr15-91181798; COSMIC: COSV51601061; COSMIC: COSV51601061;