Genetic Variant CRTC1:p.Met136Val (chr19-18747077-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_015321.3(CRTC1):c.406A>G(p.Met136Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CRTC1
NM_015321.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.24

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 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=0.045264363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC1	NM_015321.3 link	c.406A>G	p.Met136Val	missense_variant	Exon 4 of 14	ENST00000321949.13	NP_056136.2	Q6UUV9-1
CRTC1	NM_001098482.2 link	c.454A>G	p.Met152Val	missense_variant	Exon 5 of 15		NP_001091952.1	Q6UUV9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRTC1	ENST00000321949.13 link	c.406A>G	p.Met136Val	missense_variant	Exon 4 of 14	1	NM_015321.3	ENSP00000323332.7	Q6UUV9-1
CRTC1	ENST00000338797.10 link	c.454A>G	p.Met152Val	missense_variant	Exon 5 of 15	1		ENSP00000345001.5	Q6UUV9-2
CRTC1	ENST00000594658.5 link	c.283A>G	p.Met95Val	missense_variant	Exon 4 of 14	1		ENSP00000468893.1	M0QX46
CRTC1	ENST00000601916.1 link	c.181A>G	p.Met61Val	missense_variant	Exon 3 of 10	5		ENSP00000469285.1	M0QXN6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250500

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135536

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460724

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726732

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 06, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.038

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.30

DEOGEN2

Benign

0.12

T;.;.;.

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.48

T;T;T;T

M_CAP

Benign

0.0051

MetaRNN

Benign

0.045

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-2.6

N;.;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Benign

1.3

N;N;.;.

REVEL

Benign

0.11

Sift

Benign

1.0

T;T;.;.

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.25

MutPred

0.17

Gain of sheet (P = 0.0344);.;.;.;

MVP

0.043

MPC

0.58

ClinPred

0.047

GERP RS

4.8

Varity_R

0.086

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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