15-90629273-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_022769.5(CRTC3):c.1007C>T(p.Thr336Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CRTC3
NM_022769.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.71

Variant links:

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 links:

CRTC3-AS1 (HGNC:51433): (CRTC3 antisense RNA 1)

CRTC3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33926755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC3	NM_022769.5 link	c.1007C>T	p.Thr336Met	missense_variant	Exon 11 of 15	ENST00000268184.11	NP_073606.3	Q6UUV7-1Q8TEF4
CRTC3	NM_001042574.3 link	c.1007C>T	p.Thr336Met	missense_variant	Exon 11 of 15		NP_001036039.1	Q6UUV7-3Q8TEF4
CRTC3-AS1	NR_120372.1 link	n.510-9120G>A		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRTC3	ENST00000268184.11 link	c.1007C>T	p.Thr336Met	missense_variant	Exon 11 of 15	1	NM_022769.5	ENSP00000268184.6	Q6UUV7-1
CRTC3	ENST00000420329.6 link	c.1007C>T	p.Thr336Met	missense_variant	Exon 11 of 15	2		ENSP00000416573.2	Q6UUV7-3
CRTC3	ENST00000686240.1 link	n.*420C>T		non_coding_transcript_exon_variant	Exon 10 of 14			ENSP00000508866.1	A0A8I5KTH9
CRTC3	ENST00000687075.1 link	n.*243C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 9			ENSP00000510590.1	A0A8I5QJV4
CRTC3	ENST00000691029.1 link	n.1007C>T		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000510507.1	Q6UUV7-1
CRTC3	ENST00000692149.1 link	n.*334C>T		non_coding_transcript_exon_variant	Exon 9 of 13			ENSP00000510448.1	A0A8I5KTH9
CRTC3	ENST00000686240.1 link	n.*420C>T		3_prime_UTR_variant	Exon 10 of 14			ENSP00000508866.1	A0A8I5KTH9
CRTC3	ENST00000687075.1 link	n.*243C>T		3_prime_UTR_variant	Exon 9 of 9			ENSP00000510590.1	A0A8I5QJV4
CRTC3	ENST00000692149.1 link	n.*334C>T		3_prime_UTR_variant	Exon 9 of 13			ENSP00000510448.1	A0A8I5KTH9

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251384

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1007C>T (p.T336M) alteration is located in exon 11 (coding exon 11) of the CRTC3 gene. This alteration results from a C to T substitution at nucleotide position 1007, causing the threonine (T) at amino acid position 336 to be replaced by a methionine (M). 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

0.12

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

.;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.0095

MetaRNN

Benign

0.34

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.15

Sift

Uncertain

0.0090

D;D

Sift4G

Benign

0.28

T;T

Polyphen

1.0

D;D

Vest4

0.47

MutPred

0.35

Gain of catalytic residue at T336 (P = 0.0405);Gain of catalytic residue at T336 (P = 0.0405);

MVP

0.11

MPC

0.27

ClinPred

0.77

GERP RS

5.1

Varity_R

0.059

gMVP

0.51

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over