19-18768645-G-C

Variant names:

• chr19-18768645-G-C
• rs747932993
• NM_015321.3:c.1172G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015321.3(CRTC1):​c.1172G>C​(p.Arg391Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R391H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000031 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRTC1 NM_015321.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.084980905).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015321.3. 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
	CRTC1	NM_015321.3	MANE Select	c.1172G>C	p.Arg391Pro	missense	Exon 10 of 14	NP_056136.2	Q6UUV9-1
	CRTC1	NM_001098482.2		c.1220G>C	p.Arg407Pro	missense	Exon 11 of 15	NP_001091952.1	Q6UUV9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRTC1	ENST00000321949.13	TSL:1 MANE Select	c.1172G>C	p.Arg391Pro	missense	Exon 10 of 14	ENSP00000323332.7	Q6UUV9-1
	CRTC1	ENST00000338797.10	TSL:1	c.1220G>C	p.Arg407Pro	missense	Exon 11 of 15	ENSP00000345001.5	Q6UUV9-2
	CRTC1	ENST00000594658.5	TSL:1	c.1049G>C	p.Arg350Pro	missense	Exon 10 of 14	ENSP00000468893.1	M0QX46

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD2 exomes AF: 0.00000890 AC: 1 AN: 112334 AF XY: 0.0000163

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000309 AC: 3 AN: 970276 Hom.: 0 Cov.: 29 AF XY: 0.00000420 AC XY: 2 AN XY: 475944

African (AFR) AF: 0.00 AC: 0 AN: 20280

American (AMR) AF: 0.00 AC: 0 AN: 21518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13638

East Asian (EAS) AF: 0.00 AC: 0 AN: 12164

South Asian (SAS) AF: 0.0000354 AC: 2 AN: 56432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2394

European-Non Finnish (NFE) AF: 0.00000127 AC: 1 AN: 786968

Other (OTH) AF: 0.00 AC: 0 AN: 34950

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.87
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.025
Sift	Benign	0.34	T
Sift4G	Benign	0.29	T
Polyphen		0.046	B
Vest4		0.19
MutPred		0.31		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.29
MPC		0.91
ClinPred		0.088	T
GERP RS		1.2
Varity_R		0.13
gMVP		0.29
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs747932993; hg19: chr19-18879455; COSMIC: COSV105225210;