19-18745945-C-G

Position:

• chr19-18745945-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015321.3(CRTC1):​c.366C>G​(p.Asp122Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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: 0.418

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38503438).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRTC1	NM_015321.3	c.366C>G	p.Asp122Glu	missense_variant	3/14	ENST00000321949.13
CRTC1	NM_001098482.2	c.414C>G	p.Asp138Glu	missense_variant	4/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRTC1	ENST00000321949.13	c.366C>G	p.Asp122Glu	missense_variant	3/14	1	NM_015321.3	A1
CRTC1	ENST00000338797.10	c.414C>G	p.Asp138Glu	missense_variant	4/15	1		P4
CRTC1	ENST00000594658.5	c.243C>G	p.Asp81Glu	missense_variant	3/14	1
CRTC1	ENST00000601916.1	c.141C>G	p.Asp47Glu	missense_variant	2/10	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2024

The c.414C>G (p.D138E) alteration is located in exon 4 (coding exon 4) of the CRTC1 gene. This alteration results from a C to G substitution at nucleotide position 414, causing the aspartic acid (D) at amino acid position 138 to be replaced by a glutamic acid (E). 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	0.32
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.1	N;N;.;.
REVEL	Benign	0.18
Sift	Benign	0.11	T;T;.;.
Sift4G	Benign	0.24	T;T;T;T
Polyphen		0.63	P;B;.;.
Vest4		0.64
MutPred		0.16		Loss of stability (P = 0.0565);.;.;.;
MVP		0.61
MPC		0.58
ClinPred		0.41	T
GERP RS		-0.13
Varity_R		0.079
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-18856755;