Genetic Variant CRTC3:p.Pro221Pro (chr15-90617932-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_022769.5(CRTC3):c.663G>A(p.Pro221Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,612,776 control chromosomes in the GnomAD database, including 143 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 10 hom., cov: 31)

Exomes 𝑓: 0.0044 ( 133 hom. )

Consequence

CRTC3
NM_022769.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.209

Publications

6 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:

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

CRTC3-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 15-90617932-G-A is Benign according to our data. Variant chr15-90617932-G-A is described in ClinVar as Benign. ClinVar VariationId is 718782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.209 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0669 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022769.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRTC3	NM_022769.5	MANE Select	c.663G>A	p.Pro221Pro	synonymous	Exon 8 of 15	NP_073606.3	Q6UUV7-1
	CRTC3	NM_001042574.3		c.663G>A	p.Pro221Pro	synonymous	Exon 8 of 15	NP_001036039.1	Q6UUV7-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRTC3	ENST00000268184.11	TSL:1 MANE Select	c.663G>A	p.Pro221Pro	synonymous	Exon 8 of 15	ENSP00000268184.6	Q6UUV7-1
CRTC3	ENST00000420329.6	TSL:2	c.663G>A	p.Pro221Pro	synonymous	Exon 8 of 15	ENSP00000416573.2	Q6UUV7-3
CRTC3	ENST00000558005.1	TSL:4	c.318G>A	p.Pro106Pro	synonymous	Exon 5 of 7	ENSP00000452676.1	H0YK64

Frequencies

GnomAD3 genomes

AF:

0.00524

AC:

796

AN:

151850

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00446

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.0436

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0328

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00143

Gnomad OTH

AF:

0.00527

GnomAD2 exomes

AF:

0.00963

AC:

2420

AN:

251398

AF XY:

0.00891

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0147

Gnomad ASJ exome

AF:

0.00526

Gnomad EAS exome

AF:

0.0444

Gnomad FIN exome

AF:

0.0315

Gnomad NFE exome

AF:

0.00178

Gnomad OTH exome

AF:

0.00684

GnomAD4 exome

AF:

0.00441

AC:

6439

AN:

1460808

Hom.:

133

Cov.:

AF XY:

0.00435

AC XY:

3160

AN XY:

726808

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33444

American (AMR)

AF:

0.0127

AC:

568

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00628

AC:

164

AN:

26128

East Asian (EAS)

AF:

0.0690

AC:

2740

AN:

39688

South Asian (SAS)

AF:

0.00397

AC:

342

AN:

86228

European-Finnish (FIN)

AF:

0.0310

AC:

1656

AN:

53400

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000627

AC:

697

AN:

1111104

Other (OTH)

AF:

0.00426

AC:

257

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

286

572

857

1143

1429

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<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:

0.00524

AC:

796

AN:

151968

Hom.:

Cov.:

AF XY:

0.00661

AC XY:

491

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41422

American (AMR)

AF:

0.00445

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3468

East Asian (EAS)

AF:

0.0435

AC:

225

AN:

5174

South Asian (SAS)

AF:

0.00394

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0328

AC:

345

AN:

10514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00143

AC:

AN:

67988

Other (OTH)

AF:

0.00617

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

109

145

181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00194

Hom.:

Bravo

AF:

0.00336

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000830

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

-0.21

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over