chr19-18744139-C-T

Variant names:

• chr19-18744139-C-T
• rs1459932385
• ENST00000338797.10:c.275C>T

Variant summary

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

The NM_001098482.2(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. 14/20 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 NM_001098482.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.875
• Publications: 0 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=0.16942427).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098482.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRTC1	NM_015321.3	MANE Select	c.243+1113C>T		intron	N/A	NP_056136.2	Q6UUV9-1
	CRTC1	NM_001098482.2		c.275C>T	p.Ala92Val	missense	Exon 3 of 15	NP_001091952.1	Q6UUV9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRTC1	ENST00000338797.10	TSL:1	c.275C>T	p.Ala92Val	missense	Exon 3 of 15	ENSP00000345001.5	Q6UUV9-2
	CRTC1	ENST00000321949.13	TSL:1 MANE Select	c.243+1113C>T		intron	N/A	ENSP00000323332.7	Q6UUV9-1
	CRTC1	ENST00000594658.5	TSL:1	c.120+1113C>T		intron	N/A	ENSP00000468893.1	M0QX46

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 246770 AF XY: 0.00000746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44442

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 85678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111164

Other (OTH) AF: 0.00 AC: 0 AN: 60316

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
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
PhyloP100		0.88
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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs1459932385; hg19: chr19-18854949; COSMIC: COSV106097570;