15-90617932-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_022769.5(CRTC3):c.663G>A(p.Pro221=) 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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.209

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]

ACMG classification

Verdict is Benign. Variant got -15 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 id is 718782.Status of the report is criteria_provided_single_submitter, 1 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRTC3	NM_022769.5	c.663G>A	p.Pro221=	synonymous_variant	8/15	ENST00000268184.11
CRTC3	NM_001042574.3	c.663G>A	p.Pro221=	synonymous_variant	8/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRTC3	ENST00000268184.11	c.663G>A	p.Pro221=	synonymous_variant	8/15	1	NM_022769.5	P3

Frequencies

GnomAD3 genomes AF: 0.00524 AC: 796 AN: 151850 Hom.: 10 Cov.: 31

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

GnomAD3 exomes AF: 0.00963 AC: 2420 AN: 251398 Hom.: 37 AF XY: 0.00891 AC XY: 1211 AN XY: 135874

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 SAS exome AF: 0.00363

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.: 29 AF XY: 0.00435 AC XY: 3160 AN XY: 726808

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.0127

Gnomad4 ASJ exome AF: 0.00628

Gnomad4 EAS exome AF: 0.0690

Gnomad4 SAS exome AF: 0.00397

Gnomad4 FIN exome AF: 0.0310

Gnomad4 NFE exome AF: 0.000627

Gnomad4 OTH exome AF: 0.00426

GnomAD4 genome AF: 0.00524 AC: 796 AN: 151968 Hom.: 10 Cov.: 31 AF XY: 0.00661 AC XY: 491 AN XY: 74254

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.0435

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.0328

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.00617

Alfa AF: 0.00200 Hom.: 1

Bravo AF: 0.00336

Asia WGS AF: 0.0270 AC: 93 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 07, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	10
Dann	Benign	0.72

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

LitVar

Other links and lift over

dbSNP: rs77748519; hg19: chr15-91161164; COSMIC: COSV51601699; COSMIC: COSV51601699;