Genetic Variant NM_015321.3:c.880G>C (chr19-18760222-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015321.3(CRTC1):c.880G>C(p.Gly294Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G294S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CRTC1
NM_015321.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.792

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

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=0.13650596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC1	NM_015321.3 link	c.880G>C	p.Gly294Arg	missense_variant	Exon 8 of 14	ENST00000321949.13	NP_056136.2	Q6UUV9-1
CRTC1	NM_001098482.2 link	c.928G>C	p.Gly310Arg	missense_variant	Exon 9 of 15		NP_001091952.1	Q6UUV9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRTC1	ENST00000321949.13 link	c.880G>C	p.Gly294Arg	missense_variant	Exon 8 of 14	1	NM_015321.3	ENSP00000323332.7	Q6UUV9-1
CRTC1	ENST00000338797.10 link	c.928G>C	p.Gly310Arg	missense_variant	Exon 9 of 15	1		ENSP00000345001.5	Q6UUV9-2
CRTC1	ENST00000594658.5 link	c.757G>C	p.Gly253Arg	missense_variant	Exon 8 of 14	1		ENSP00000468893.1	M0QX46
CRTC1	ENST00000601916.1 link	c.655G>C	p.Gly219Arg	missense_variant	Exon 7 of 10	5		ENSP00000469285.1	M0QXN6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445908

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718610

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33116

American (AMR)

AF:

0.00

AC:

AN:

41592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25826

East Asian (EAS)

AF:

0.00

AC:

AN:

38914

South Asian (SAS)

AF:

0.00

AC:

AN:

85176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105284

Other (OTH)

AF:

0.00

AC:

AN:

59868

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

T;.;.;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.69

T;T;T;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.;.;.

PhyloP100

0.79

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.7

D;D;.;.

REVEL

Benign

0.039

Sift

Benign

0.049

D;D;.;.

Sift4G

Uncertain

0.020

D;T;D;T

Polyphen

0.41

B;B;.;.

Vest4

0.45

MutPred

0.23

Gain of MoRF binding (P = 0.0353);.;.;.;

MVP

0.35

MPC

1.0

ClinPred

0.43

GERP RS

-0.76

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.12

gMVP

0.20

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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NM_015321.3:c.880G>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over