19-18777344-C-T

Variant names:

• chr19-18777344-C-T
• rs762168920
• NM_015321.3:c.1867C>T

Variant summary

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

The NM_015321.3(CRTC1):​c.1867C>T​(p.Pro623Ser) 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: 33)
• Consequence: CRTC1 NM_015321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84
• 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.1867C>T	p.Pro623Ser	missense_variant	Exon 14 of 14	ENST00000321949.13	NP_056136.2
CRTC1	NM_001098482.2	c.1915C>T	p.Pro639Ser	missense_variant	Exon 15 of 15		NP_001091952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTC1	ENST00000321949.13	c.1867C>T	p.Pro623Ser	missense_variant	Exon 14 of 14	1	NM_015321.3	ENSP00000323332.7
CRTC1	ENST00000338797.10	c.1915C>T	p.Pro639Ser	missense_variant	Exon 15 of 15	1		ENSP00000345001.5
CRTC1	ENST00000594658.5	c.1744C>T	p.Pro582Ser	missense_variant	Exon 14 of 14	1		ENSP00000468893.1
CRTC1	ENST00000601916.1	c.1141C>T	p.Pro381Ser	missense_variant	Exon 10 of 10	5		ENSP00000469285.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1915C>T (p.P639S) alteration is located in exon 15 (coding exon 15) of the CRTC1 gene. This alteration results from a C to T substitution at nucleotide position 1915, causing the proline (P) at amino acid position 639 to be replaced by a serine (S). 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	Benign	0.16
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;.;.;.
PhyloP100		5.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.9	D;D;.;.
REVEL	Uncertain	0.34
Sift	Benign	0.057	T;T;.;.
Sift4G	Uncertain	0.045	D;D;T;T
Polyphen		0.35	B;P;.;.
Vest4		0.78
MutPred		0.47		Gain of relative solvent accessibility (P = 0.0289);.;.;.;
MVP		0.75
MPC		1.5
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.69
Mutation Taster		=51/49	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: rs762168920; hg19: chr19-18888154;