chr19-18768654-C-T

Position:

• chr19-18768654-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000321949.13(CRTC1):​c.1181C>T​(p.Pro394Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,388,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CRTC1 ENST00000321949.13 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.097244024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRTC1	NM_015321.3	c.1181C>T	p.Pro394Leu	missense_variant	10/14	ENST00000321949.13	NP_056136.2
CRTC1	NM_001098482.2	c.1229C>T	p.Pro410Leu	missense_variant	11/15		NP_001091952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRTC1	ENST00000321949.13	c.1181C>T	p.Pro394Leu	missense_variant	10/14	1	NM_015321.3	ENSP00000323332	A1
CRTC1	ENST00000338797.10	c.1229C>T	p.Pro410Leu	missense_variant	11/15	1		ENSP00000345001	P4
CRTC1	ENST00000594658.5	c.1058C>T	p.Pro353Leu	missense_variant	10/14	1		ENSP00000468893
CRTC1	ENST00000601916.1	c.786+3126C>T		intron_variant		5		ENSP00000469285

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1388246 Hom.: 0 Cov.: 32 AF XY: 0.00000146 AC XY: 1 AN XY: 684982

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Sep 27, 2021

The c.1229C>T (p.P410L) alteration is located in exon 11 (coding exon 11) of the CRTC1 gene. This alteration results from a C to T substitution at nucleotide position 1229, causing the proline (P) at amino acid position 410 to be replaced by a leucine (L). 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	0.097
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.30	T;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.097	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.76	N;.;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.0	N;N;.
REVEL	Benign	0.037
Sift	Benign	0.045	D;D;.
Sift4G	Benign	0.12	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.14
MutPred		0.31		Loss of relative solvent accessibility (P = 0.008);.;.;
MVP		0.10
MPC		0.63
ClinPred		0.11	T
GERP RS		-2.0
Varity_R		0.026
gMVP		0.16

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-18879464;