Genetic Variant NM_015321.3:c.712G>A (chr19-18760054-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_015321.3(CRTC1):c.712G>A(p.Ala238Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000015 in 1,599,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CRTC1
NM_015321.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.49

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23581684).

BS2

High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC1	NM_015321.3 link	c.712G>A	p.Ala238Thr	missense_variant	Exon 8 of 14	ENST00000321949.13	NP_056136.2	Q6UUV9-1
CRTC1	NM_001098482.2 link	c.760G>A	p.Ala254Thr	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.712G>A	p.Ala238Thr	missense_variant	Exon 8 of 14	1	NM_015321.3	ENSP00000323332.7	Q6UUV9-1
CRTC1	ENST00000338797.10 link	c.760G>A	p.Ala254Thr	missense_variant	Exon 9 of 15	1		ENSP00000345001.5	Q6UUV9-2
CRTC1	ENST00000594658.5 link	c.589G>A	p.Ala197Thr	missense_variant	Exon 8 of 14	1		ENSP00000468893.1	M0QX46
CRTC1	ENST00000601916.1 link	c.487G>A	p.Ala163Thr	missense_variant	Exon 7 of 10	5		ENSP00000469285.1	M0QXN6

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

149914

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000249

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:

0.00

Gnomad OTH

AF:

0.000486

GnomAD2 exomes

AF:

0.0000282

AC:

AN:

248004

AF XY:

0.0000373

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000903

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000145

AC:

AN:

1449088

Hom.:

Cov.:

AF XY:

0.0000236

AC XY:

AN XY:

720034

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32712

American (AMR)

AF:

0.00

AC:

AN:

44354

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25634

East Asian (EAS)

AF:

0.00

AC:

AN:

38918

South Asian (SAS)

AF:

0.000163

AC:

AN:

86024

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52760

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00000544

AC:

AN:

1103450

Other (OTH)

AF:

0.00

AC:

AN:

59536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000200

AC:

AN:

150022

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

73256

show subpopulations

African (AFR)

AF:

0.0000248

AC:

AN:

40340

American (AMR)

AF:

0.00

AC:

AN:

15082

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5078

South Asian (SAS)

AF:

0.000212

AC:

AN:

4728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67716

Other (OTH)

AF:

0.000480

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.760G>A (p.A254T) alteration is located in exon 9 (coding exon 9) of the CRTC1 gene. This alteration results from a G to A substitution at nucleotide position 760, causing the alanine (A) at amino acid position 254 to be replaced by a threonine (T). 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

0.087

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.;.;.

Eigen

Benign

0.021

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

T;D;T;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.24

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.6

M;.;.;.

PhyloP100

6.5

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.0

N;N;.;.

REVEL

Benign

0.096

Sift

Benign

0.19

T;T;.;.

Sift4G

Benign

0.088

T;T;T;T

Polyphen

0.14

B;B;.;.

Vest4

0.39

MutPred

0.22

Gain of glycosylation at A238 (P = 9e-04);.;.;.;

MVP

0.50

MPC

0.57

ClinPred

0.46

GERP RS

3.5

Varity_R

0.12

gMVP

0.46

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_015321.3:c.712G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over