chr19-18744139-C-T

Position:

• chr19-18744139-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000338797.10(CRTC1):​c.275C>T​(p.Ala92Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CRTC1 ENST00000338797.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.875

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16942427).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRTC1	NM_015321.3	c.243+1113C>T		intron_variant		ENST00000321949.13
CRTC1	NM_001098482.2	c.275C>T	p.Ala92Val	missense_variant	3/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRTC1	ENST00000338797.10	c.275C>T	p.Ala92Val	missense_variant	3/15	1		P4
CRTC1	ENST00000321949.13	c.243+1113C>T		intron_variant		1	NM_015321.3	A1
CRTC1	ENST00000594658.5	c.120+1113C>T		intron_variant		1
CRTC1	ENST00000601916.1	c.18+1113C>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459688 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2022

The c.275C>T (p.A92V) alteration is located in exon 3 (coding exon 3) of the CRTC1 gene. This alteration results from a C to T substitution at nucleotide position 275, causing the alanine (A) at amino acid position 92 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
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Uncertain	1.0
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.034
Sift	Uncertain	0.022	D
Sift4G	Benign	0.15	T
Polyphen		0.66	P
Vest4		0.32
MutPred		0.29		Loss of helix (P = 0.0237);
MVP		0.12
MPC		0.61
ClinPred		0.39	T
GERP RS		2.5
gMVP		0.52

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

Other links and lift over

dbSNP: rs1459932385; hg19: chr19-18854949;