Variant chr19-18768645-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_015321.3(CRTC1):c.1172G>A(p.Arg391His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 970,336 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 27)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CRTC1
NM_015321.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.17

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10142225).

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRTC1	NM_015321.3 linkuse as main transcript	c.1172G>A	p.Arg391His	missense_variant	10/14	ENST00000321949.13
CRTC1	NM_001098482.2 linkuse as main transcript	c.1220G>A	p.Arg407His	missense_variant	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRTC1	ENST00000321949.13 linkuse as main transcript	c.1172G>A	p.Arg391His	missense_variant	10/14	1	NM_015321.3	A1	Q6UUV9-1
CRTC1	ENST00000338797.10 linkuse as main transcript	c.1220G>A	p.Arg407His	missense_variant	11/15	1		P4	Q6UUV9-2
CRTC1	ENST00000594658.5 linkuse as main transcript	c.1049G>A	p.Arg350His	missense_variant	10/14	1
CRTC1	ENST00000601916.1 linkuse as main transcript	c.786+3117G>A		intron_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000890

AC:

AN:

112334

Hom.:

AF XY:

0.00

AC XY:

AN XY:

61486

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:

0.0000549

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000124

AC:

AN:

970336

Hom.:

Cov.:

AF XY:

0.0000105

AC XY:

AN XY:

475970

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:

0.0000532

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000102

Gnomad4 OTH exome

AF:

0.0000286

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000983

AC:

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 20, 2023

The c.1220G>A (p.R407H) alteration is located in exon 11 (coding exon 11) of the CRTC1 gene. This alteration results from a G to A substitution at nucleotide position 1220, causing the arginine (R) at amino acid position 407 to be replaced by a histidine (H). 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

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;.;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.74

T;T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.27

N;N;.

REVEL

Benign

0.016

Sift

Benign

0.16

T;T;.

Sift4G

Benign

0.15

T;T;T

Polyphen

0.31

B;B;.

Vest4

0.14

MutPred

0.32

Loss of methylation at R391 (P = 0.0171);.;.;

MVP

0.42

MPC

0.87

ClinPred

0.24

GERP RS

1.2

Varity_R

0.031

gMVP

0.12

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