chr19-18747078-T-G

Variant names:

• chr19-18747078-T-G
• NM_015321.3:c.407T>G

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.407T>G​(p.Met136Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M136V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CRTC1 NM_015321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39
• 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=0.23635724).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC1	NM_015321.3	c.407T>G	p.Met136Arg	missense_variant	Exon 4 of 14	ENST00000321949.13	NP_056136.2
CRTC1	NM_001098482.2	c.455T>G	p.Met152Arg	missense_variant	Exon 5 of 15		NP_001091952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTC1	ENST00000321949.13	c.407T>G	p.Met136Arg	missense_variant	Exon 4 of 14	1	NM_015321.3	ENSP00000323332.7
CRTC1	ENST00000338797.10	c.455T>G	p.Met152Arg	missense_variant	Exon 5 of 15	1		ENSP00000345001.5
CRTC1	ENST00000594658.5	c.284T>G	p.Met95Arg	missense_variant	Exon 4 of 14	1		ENSP00000468893.1
CRTC1	ENST00000601916.1	c.182T>G	p.Met61Arg	missense_variant	Exon 3 of 10	5		ENSP00000469285.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

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 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.455T>G (p.M152R) alteration is located in exon 5 (coding exon 5) of the CRTC1 gene. This alteration results from a T to G substitution at nucleotide position 455, causing the methionine (M) at amino acid position 152 to be replaced by an arginine (R). 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	Pathogenic	0.61
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Uncertain	0.97
DEOGEN2	Benign	0.33	T;.;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.10
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;D;T;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N;.;.;.
PhyloP100		7.4
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.2	N;N;.;.
REVEL	Benign	0.13
Sift	Benign	0.24	T;T;.;.
Sift4G	Uncertain	0.020	D;D;D;D
Polyphen		0.0010	B;B;.;.
Vest4		0.41
MutPred		0.20		Gain of solvent accessibility (P = 0.0584);.;.;.;
MVP		0.12
MPC		0.95
ClinPred		0.92	D
GERP RS		4.8
Varity_R		0.64
gMVP		0.36
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr19-18857888;