chr19-18760188-G-A

Position:

• chr19-18760188-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_015321.3(CRTC1):​c.846G>A​(p.Ala282Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,612,908 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (26 hom.)
• Consequence: CRTC1 NM_015321.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.97

Genes affected

CRTC1 (HGNC:16062): (CREB regulated transcription coactivator 1) Enables cAMP response element binding protein binding activity. Involved in positive regulation of transcription by RNA polymerase II. Located in cytosol; nuclear body; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 19-18760188-G-A is Benign according to our data. Variant chr19-18760188-G-A is described in ClinVar as [Benign]. Clinvar id is 788467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.97 with no splicing effect.
• BS2: High AC in GnomAd4 at 868 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRTC1	NM_015321.3	c.846G>A	p.Ala282Ala	synonymous_variant	8/14	ENST00000321949.13	NP_056136.2
CRTC1	NM_001098482.2	c.894G>A	p.Ala298Ala	synonymous_variant	9/15		NP_001091952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRTC1	ENST00000321949.13	c.846G>A	p.Ala282Ala	synonymous_variant	8/14	1	NM_015321.3	ENSP00000323332.7
CRTC1	ENST00000338797.10	c.894G>A	p.Ala298Ala	synonymous_variant	9/15	1		ENSP00000345001.5
CRTC1	ENST00000594658.5	c.723G>A	p.Ala241Ala	synonymous_variant	8/14	1		ENSP00000468893.1
CRTC1	ENST00000601916.1	c.621G>A	p.Ala207Ala	synonymous_variant	7/10	5		ENSP00000469285.1

Frequencies

GnomAD3 genomes AF: 0.00569 AC: 866 AN: 152134 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0157

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00346 AC: 845 AN: 244182 Hom.: 9 AF XY: 0.00367 AC XY: 487 AN XY: 132684

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.0165

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.0116

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000303

Gnomad OTH exome AF: 0.00251

GnomAD4 exome AF: 0.00164 AC: 2392 AN: 1460656 Hom.: 26 Cov.: 33 AF XY: 0.00196 AC XY: 1425 AN XY: 726658

Gnomad4 AFR exome AF: 0.0157

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.0156

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000136

Gnomad4 OTH exome AF: 0.00312

GnomAD4 genome AF: 0.00570 AC: 868 AN: 152252 Hom.: 8 Cov.: 32 AF XY: 0.00574 AC XY: 427 AN XY: 74438

Gnomad4 AFR AF: 0.0159

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0157

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00328 Hom.: 3

Bravo AF: 0.00567

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.8
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs112538945; hg19: chr19-18870998;