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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC1	NM_015321.3	c.712G>C	p.Ala238Pro	missense_variant	Exon 8 of 14	ENST00000321949.13	NP_056136.2
CRTC1	NM_001098482.2	c.760G>C	p.Ala254Pro	missense_variant	Exon 9 of 15		NP_001091952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTC1	ENST00000321949.13	c.712G>C	p.Ala238Pro	missense_variant	Exon 8 of 14	1	NM_015321.3	ENSP00000323332.7
CRTC1	ENST00000338797.10	c.760G>C	p.Ala254Pro	missense_variant	Exon 9 of 15	1		ENSP00000345001.5
CRTC1	ENST00000594658.5	c.589G>C	p.Ala197Pro	missense_variant	Exon 8 of 14	1		ENSP00000468893.1
CRTC1	ENST00000601916.1	c.487G>C	p.Ala163Pro	missense_variant	Exon 7 of 10	5		ENSP00000469285.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;D;T;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.55	D;D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.9	L;.;.;.
PhyloP100		6.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.5	N;N;.;.
REVEL	Benign	0.19
Sift	Benign	0.29	T;T;.;.
Sift4G	Benign	0.44	T;T;T;T
Polyphen		0.99	D;P;.;.
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;