19-18683811-C-G

Variant names:

• chr19-18683811-C-G
• NM_015321.3:c.109C>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_015321.3(CRTC1):​c.109C>G​(p.Leu37Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000068 in 1,175,850 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: CRTC1 NM_015321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06091082).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC1	NM_015321.3	c.109C>G	p.Leu37Val	missense_variant	Exon 1 of 14	ENST00000321949.13	NP_056136.2
CRTC1	NM_001098482.2	c.109C>G	p.Leu37Val	missense_variant	Exon 1 of 15		NP_001091952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTC1	ENST00000321949.13	c.109C>G	p.Leu37Val	missense_variant	Exon 1 of 14	1	NM_015321.3	ENSP00000323332.7
CRTC1	ENST00000338797.10	c.109C>G	p.Leu37Val	missense_variant	Exon 1 of 15	1		ENSP00000345001.5

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000680 AC: 8 AN: 1175850 Hom.: 0 Cov.: 32 AF XY: 0.00000518 AC XY: 3 AN XY: 578878

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: 0.00000637

Gnomad4 OTH exome AF: 0.0000458

GnomAD4 genome Cov.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.109C>G (p.L37V) alteration is located in exon 1 (coding exon 1) of the CRTC1 gene. This alteration results from a C to G substitution at nucleotide position 109, causing the leucine (L) at amino acid position 37 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	0.079
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	22
DANN	Benign	0.86
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.061	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.17	N;N
REVEL	Benign	0.038
Sift	Benign	0.59	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.028	B;B
Vest4		0.13
MutPred		0.20		Gain of MoRF binding (P = 0.0818);Gain of MoRF binding (P = 0.0818);
MVP		0.082
MPC		1.8
ClinPred		0.26	T
GERP RS		3.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.11
gMVP		0.20

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: chr19-18794621;