chr1-153949209-C-T

Variant names:

• chr1-153949209-C-T
• rs762975258
• NM_181715.3:c.1580G>A

Variant summary

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

The NM_181715.3(CRTC2):​c.1580G>A​(p.Arg527Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R527T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRTC2 NM_181715.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.75

Genes affected

CRTC2 (HGNC:27301): (CREB regulated transcription coactivator 2) This gene encodes a member of the transducers of regulated cAMP response element-binding protein activity family of transcription coactivators. These proteins promote the transcription of genes targeted by the cAMP response element-binding protein, and therefore play an important role in many cellular processes. Under basal conditions the encoded protein is phosphorylated by AMP-activated protein kinase or the salt-inducible kinases and is sequestered in the cytoplasm. Upon activation by elevated cAMP or calcium, the encoded protein translocates to the nucleus and increases target gene expression. Single nucleotide polymorphisms in this gene may increase the risk of type 2 diabetes. A pseudogene of this gene is located on the long arm of chromosome 5. [provided by RefSeq, Dec 2010]

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=0.13020656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC2	NM_181715.3	c.1580G>A	p.Arg527Lys	missense_variant	Exon 12 of 14	ENST00000368633.2	NP_859066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTC2	ENST00000368633.2	c.1580G>A	p.Arg527Lys	missense_variant	Exon 12 of 14	1	NM_181715.3	ENSP00000357622.1
CRTC2	ENST00000461638.6	n.1340G>A		non_coding_transcript_exon_variant	Exon 10 of 13	1		ENSP00000434115.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Benign	0.71
DEOGEN2	Benign	0.32	.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	.;L
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.18	N;N
REVEL	Benign	0.087
Sift	Benign	0.34	T;T
Sift4G	Benign	0.93	T;T
Polyphen		0.92	P;B
Vest4		0.41
MutPred		0.21		.;Gain of ubiquitination at R527 (P = 0.0051);
MVP		0.42
MPC		0.71
ClinPred		0.18	T
GERP RS		4.7
Varity_R		0.088
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs762975258; hg19: chr1-153921685;