Variant 19-18745900-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000321949.13(CRTC1):c.321G>C(p.Glu107Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,246 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CRTC1
ENST00000321949.13 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.220

Variant links:

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]

CRTC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054432154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRTC1	NM_015321.3 linkuse as main transcript	c.321G>C	p.Glu107Asp	missense_variant	3/14	ENST00000321949.13	NP_056136.2
CRTC1	NM_001098482.2 linkuse as main transcript	c.369G>C	p.Glu123Asp	missense_variant	4/15		NP_001091952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRTC1	ENST00000321949.13 linkuse as main transcript	c.321G>C	p.Glu107Asp	missense_variant	3/14	1	NM_015321.3	ENSP00000323332	A1	Q6UUV9-1
CRTC1	ENST00000338797.10 linkuse as main transcript	c.369G>C	p.Glu123Asp	missense_variant	4/15	1		ENSP00000345001	P4	Q6UUV9-2
CRTC1	ENST00000594658.5 linkuse as main transcript	c.198G>C	p.Glu66Asp	missense_variant	3/14	1		ENSP00000468893
CRTC1	ENST00000601916.1 linkuse as main transcript	c.96G>C	p.Glu32Asp	missense_variant	2/10	5		ENSP00000469285

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461004

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726826

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2023

The c.369G>C (p.E123D) alteration is located in exon 4 (coding exon 4) of the CRTC1 gene. This alteration results from a G to C substitution at nucleotide position 369, causing the glutamic acid (E) at amino acid position 123 to be replaced by an aspartic acid (D). 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

0.083

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.12

T;.;.;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.52

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Benign

0.0030

MetaRNN

Benign

0.054

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.60

N;.;.;.

MutationTaster

Benign

0.89

D;D

PrimateAI

Uncertain

0.72

PROVEAN

Benign

1.1

N;N;.;.

REVEL

Benign

0.12

Sift

Benign

0.81

T;T;.;.

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0010

B;B;.;.

Vest4

0.16

MutPred

0.21

Gain of sheet (P = 0.039);.;.;.;

MVP

0.21

MPC

0.53

ClinPred

0.058

GERP RS

-4.2

Varity_R

0.12

gMVP

0.21

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over