19-18760054-G-C

Variant names:

• chr19-18760054-G-C
• rs746942608
• NM_015321.3:c.712G>C

Variant summary

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

The NM_015321.3(CRTC1):​c.712G>C​(p.Ala238Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. A238T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRTC1 NM_015321.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.49
• Publications: 2 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.712G>C	p.Ala238Pro	missense	Exon 8 of 14	NP_056136.2	Q6UUV9-1
	CRTC1	NM_001098482.2		c.760G>C	p.Ala254Pro	missense	Exon 9 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.712G>C	p.Ala238Pro	missense	Exon 8 of 14	ENSP00000323332.7	Q6UUV9-1
	CRTC1	ENST00000338797.10	TSL:1	c.760G>C	p.Ala254Pro	missense	Exon 9 of 15	ENSP00000345001.5	Q6UUV9-2
	CRTC1	ENST00000594658.5	TSL:1	c.589G>C	p.Ala197Pro	missense	Exon 8 of 14	ENSP00000468893.1	M0QX46

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.9	L
PhyloP100		6.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.19
Sift	Benign	0.29	T
Sift4G	Benign	0.44	T
Polyphen		0.99	D
Vest4		0.84
MutPred		0.25		Gain of catalytic residue at P237 (P = 0.0139)
MVP		0.60
MPC		0.80
ClinPred		0.88	D
GERP RS		3.5
Varity_R		0.38
gMVP		0.58
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: 16

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746942608; hg19: chr19-18870864;