chr19-18747096-C-T

Variant names:

• chr19-18747096-C-T
• rs759854241
• NM_015321.3:c.425C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_015321.3(CRTC1):​c.425C>T​(p.Ala142Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,610,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000073 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: CRTC1 NM_015321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.29
• Publications: 1 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.16375762).
• BS2: High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC1	NM_015321.3	c.425C>T	p.Ala142Val	missense_variant	Exon 4 of 14	ENST00000321949.13	NP_056136.2
CRTC1	NM_001098482.2	c.473C>T	p.Ala158Val	missense_variant	Exon 5 of 15		NP_001091952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTC1	ENST00000321949.13	c.425C>T	p.Ala142Val	missense_variant	Exon 4 of 14	1	NM_015321.3	ENSP00000323332.7
CRTC1	ENST00000338797.10	c.473C>T	p.Ala158Val	missense_variant	Exon 5 of 15	1		ENSP00000345001.5
CRTC1	ENST00000594658.5	c.302C>T	p.Ala101Val	missense_variant	Exon 4 of 14	1		ENSP00000468893.1
CRTC1	ENST00000601916.1	c.200C>T	p.Ala67Val	missense_variant	Exon 3 of 10	5		ENSP00000469285.1

Frequencies

GnomAD3 genomes AF: 0.0000732 AC: 11 AN: 150314 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000332

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: 0.0000590

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.0000240 AC: 6 AN: 249986 AF XY: 0.0000148

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460222 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 726484

African (AFR) AF: 0.0000598 AC: 2 AN: 33418

American (AMR) AF: 0.000112 AC: 5 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111028

Other (OTH) AF: 0.0000166 AC: 1 AN: 60312

GnomAD4 genome AF: 0.0000732 AC: 11 AN: 150314 Hom.: 0 Cov.: 30 AF XY: 0.0000955 AC XY: 7 AN XY: 73264

African (AFR) AF: 0.0000246 AC: 1 AN: 40666

American (AMR) AF: 0.000332 AC: 5 AN: 15076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5072

South Asian (SAS) AF: 0.00 AC: 0 AN: 4748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000590 AC: 4 AN: 67748

Other (OTH) AF: 0.000484 AC: 1 AN: 2066

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.473C>T (p.A158V) alteration is located in exon 5 (coding exon 5) of the CRTC1 gene. This alteration results from a C to T substitution at nucleotide position 473, causing the alanine (A) at amino acid position 158 to be replaced by a valine (V). 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	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.;.;.
Eigen	Benign	-0.097
Eigen_PC	Benign	0.076
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.1	L;.;.;.
PhyloP100		7.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.5	N;N;.;.
REVEL	Benign	0.13
Sift	Benign	0.12	T;T;.;.
Sift4G	Benign	0.14	T;T;D;T
Polyphen		0.53	P;B;.;.
Vest4		0.27
MutPred		0.065		Loss of relative solvent accessibility (P = 0.0676);.;.;.;
MVP		0.28
MPC		0.68
ClinPred		0.47	T
GERP RS		4.8
Varity_R		0.14
gMVP		0.15
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs759854241; hg19: chr19-18857906;