19-18768599-G-T

Variant names:

• chr19-18768599-G-T
• NM_015321.3:c.1126G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015321.3(CRTC1):​c.1126G>T​(p.Ala376Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000306 in 1,306,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 32)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: CRTC1 NM_015321.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.627

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07788554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC1	NM_015321.3	c.1126G>T	p.Ala376Ser	missense_variant	Exon 10 of 14	ENST00000321949.13	NP_056136.2
CRTC1	NM_001098482.2	c.1174G>T	p.Ala392Ser	missense_variant	Exon 11 of 15		NP_001091952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTC1	ENST00000321949.13	c.1126G>T	p.Ala376Ser	missense_variant	Exon 10 of 14	1	NM_015321.3	ENSP00000323332.7
CRTC1	ENST00000338797.10	c.1174G>T	p.Ala392Ser	missense_variant	Exon 11 of 15	1		ENSP00000345001.5
CRTC1	ENST00000594658.5	c.1003G>T	p.Ala335Ser	missense_variant	Exon 10 of 14	1		ENSP00000468893.1
CRTC1	ENST00000601916.1	c.786+3071G>T		intron_variant	Intron 8 of 9	5		ENSP00000469285.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000306 AC: 4 AN: 1306216 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 646192

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: 0.00000297

Gnomad4 OTH exome AF: 0.0000188

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	3.5
DANN	Benign	0.84
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.34	T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.078	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.20	N;N;.
REVEL	Benign	0.062
Sift	Benign	0.15	T;T;.
Sift4G	Benign	0.48	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.21
MutPred		0.33		Gain of phosphorylation at A376 (P = 7e-04);.;.;
MVP		0.51
MPC		0.61
ClinPred		0.042	T
GERP RS		0.43
Varity_R		0.093
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-18879409;