Genetic Variant CRTC3:c.133-402T>C (chr15-90539637-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_022769.5(CRTC3):c.133-402T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.881 in 249,370 control chromosomes in the GnomAD database, including 97,176 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.88 ( 59598 hom., cov: 32)

Exomes 𝑓: 0.88 ( 37578 hom. )

Consequence

CRTC3
NM_022769.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.844

Publications

8 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC3	NM_022769.5 link	c.133-402T>C		intron_variant	Intron 1 of 14	ENST00000268184.11	NP_073606.3
CRTC3	NM_001042574.3 link	c.133-402T>C		intron_variant	Intron 1 of 14		NP_001036039.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CRTC3	ENST00000268184.11 link	c.133-402T>C	intron_variant	Intron 1 of 14	1	NM_022769.5	ENSP00000268184.6
CRTC3	ENST00000420329.6 link	c.133-402T>C	intron_variant	Intron 1 of 14	2		ENSP00000416573.2
CRTC3	ENST00000686240.1 link	n.133-402T>C	intron_variant	Intron 1 of 13			ENSP00000508866.1
CRTC3	ENST00000691029.1 link	n.133-402T>C	intron_variant	Intron 1 of 16			ENSP00000510507.1
CRTC3	ENST00000692149.1 link	n.133-402T>C	intron_variant	Intron 1 of 12			ENSP00000510448.1

Frequencies

GnomAD3 genomes

AF:

0.883

AC:

134320

AN:

152104

Hom.:

59547

Cov.:

show subpopulations

Gnomad AFR

AF:

0.899

Gnomad AMI

AF:

0.954

Gnomad AMR

AF:

0.829

Gnomad ASJ

AF:

0.933

Gnomad EAS

AF:

0.692

Gnomad SAS

AF:

0.767

Gnomad FIN

AF:

0.879

Gnomad MID

AF:

0.921

Gnomad NFE

AF:

0.905

Gnomad OTH

AF:

0.898

GnomAD4 exome

AF:

0.877

AC:

85194

AN:

97148

Hom.:

37578

Cov.:

AF XY:

0.865

AC XY:

45046

AN XY:

52098

show subpopulations

African (AFR)

AF:

0.880

AC:

621

AN:

706

American (AMR)

AF:

0.798

AC:

1887

AN:

2364

Ashkenazi Jewish (ASJ)

AF:

0.924

AC:

2162

AN:

2340

East Asian (EAS)

AF:

0.701

AC:

943

AN:

1346

South Asian (SAS)

AF:

0.780

AC:

13753

AN:

17638

European-Finnish (FIN)

AF:

0.886

AC:

5454

AN:

6156

Middle Eastern (MID)

AF:

0.926

AC:

376

AN:

406

European-Non Finnish (NFE)

AF:

0.908

AC:

55253

AN:

60856

Other (OTH)

AF:

0.889

AC:

4745

AN:

5336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

481

961

1442

1922

2403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

130

260

390

520

650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.883

AC:

134426

AN:

152222

Hom.:

59598

Cov.:

AF XY:

0.878

AC XY:

65354

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.899

AC:

37345

AN:

41534

American (AMR)

AF:

0.828

AC:

12652

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.933

AC:

3238

AN:

3472

East Asian (EAS)

AF:

0.693

AC:

3590

AN:

5178

South Asian (SAS)

AF:

0.768

AC:

3707

AN:

4824

European-Finnish (FIN)

AF:

0.879

AC:

9307

AN:

10594

Middle Eastern (MID)

AF:

0.922

AC:

271

AN:

294

European-Non Finnish (NFE)

AF:

0.905

AC:

61553

AN:

68018

Other (OTH)

AF:

0.897

AC:

1893

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

800

1600

2401

3201

4001

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

898

1796

2694

3592

4490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.894

Hom.:

104577

Bravo

AF:

0.882

Asia WGS

AF:

0.743

AC:

2583

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

6.4

(source)

DANN

Benign

0.57

PhyloP100

0.84

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over