chr19-18753512-C-A

Variant names:

• chr19-18753512-C-A
• NM_015321.3:c.551C>A

Variant summary

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

The NM_015321.3(CRTC1):​c.551C>A​(p.Thr184Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CRTC1 NM_015321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.07
• 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 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.551C>A	p.Thr184Lys	missense_variant	Exon 6 of 14	ENST00000321949.13	NP_056136.2
CRTC1	NM_001098482.2	c.599C>A	p.Thr200Lys	missense_variant	Exon 7 of 15		NP_001091952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTC1	ENST00000321949.13	c.551C>A	p.Thr184Lys	missense_variant	Exon 6 of 14	1	NM_015321.3	ENSP00000323332.7
CRTC1	ENST00000338797.10	c.599C>A	p.Thr200Lys	missense_variant	Exon 7 of 15	1		ENSP00000345001.5
CRTC1	ENST00000594658.5	c.428C>A	p.Thr143Lys	missense_variant	Exon 6 of 14	1		ENSP00000468893.1
CRTC1	ENST00000601916.1	c.326C>A	p.Thr109Lys	missense_variant	Exon 5 of 10	5		ENSP00000469285.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.599C>A (p.T200K) alteration is located in exon 7 (coding exon 7) of the CRTC1 gene. This alteration results from a C to A substitution at nucleotide position 599, causing the threonine (T) at amino acid position 200 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T;.;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.57	D;D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.5	M;.;.;.
PhyloP100		7.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.9	N;N;.;.
REVEL	Benign	0.26
Sift	Benign	0.47	T;T;.;.
Sift4G	Benign	0.75	T;T;T;T
Polyphen		0.97	D;P;.;.
Vest4		0.70
MutPred		0.32		Gain of ubiquitination at T184 (P = 0.0037);.;.;.;
MVP		0.62
MPC		0.77
ClinPred		0.91	D
GERP RS		4.7
Varity_R		0.39
gMVP		0.43
Mutation Taster		=33/67	disease causing

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

hg19: chr19-18864322;