Genetic Variant CRTC1:p.Lys178Asn (chr19-18749871-A-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_015321.3(CRTC1):c.534A>T(p.Lys178Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,404 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CRTC1
NM_015321.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.960

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC1	NM_015321.3 link	c.534A>T	p.Lys178Asn	missense_variant	Exon 5 of 14	ENST00000321949.13	NP_056136.2	Q6UUV9-1
CRTC1	NM_001098482.2 link	c.582A>T	p.Lys194Asn	missense_variant	Exon 6 of 15		NP_001091952.1	Q6UUV9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRTC1	ENST00000321949.13 link	c.534A>T	p.Lys178Asn	missense_variant	Exon 5 of 14	1	NM_015321.3	ENSP00000323332.7	Q6UUV9-1
CRTC1	ENST00000338797.10 link	c.582A>T	p.Lys194Asn	missense_variant	Exon 6 of 15	1		ENSP00000345001.5	Q6UUV9-2
CRTC1	ENST00000594658.5 link	c.411A>T	p.Lys137Asn	missense_variant	Exon 5 of 14	1		ENSP00000468893.1	M0QX46
CRTC1	ENST00000601916.1 link	c.309A>T	p.Lys103Asn	missense_variant	Exon 4 of 10	5		ENSP00000469285.1	M0QXN6

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

250680

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1461248

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726940

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.0000671

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53304

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1111554

Other (OTH)

AF:

0.0000331

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41428

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 10, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.582A>T (p.K194N) alteration is located in exon 6 (coding exon 6) of the CRTC1 gene. This alteration results from a A to T substitution at nucleotide position 582, causing the lysine (K) at amino acid position 194 to be replaced by an asparagine (N). 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

Pathogenic

0.77

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;.;.;.

Eigen

Benign

0.082

Eigen_PC

Benign

0.030

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Benign

0.037

MetaRNN

Uncertain

0.48

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.6

M;.;.;.

PhyloP100

0.96

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.9

N;N;.;.

REVEL

Benign

0.12

Sift

Benign

0.13

T;T;.;.

Sift4G

Benign

0.098

T;T;T;T

Polyphen

0.97

D;P;.;.

Vest4

0.66

MutPred

0.30

Loss of ubiquitination at K178 (P = 0.0056);.;.;.;

MVP

0.58

MPC

1.6

ClinPred

0.41

GERP RS

1.4

Varity_R

0.17

gMVP

0.30

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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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19-18749871-A-T

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