19-18765436-C-T

Variant names:

• chr19-18765436-C-T
• rs1274858564
• NM_015321.3:c.919C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_015321.3(CRTC1):​c.919C>T​(p.Arg307Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CRTC1 NM_015321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.89

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 -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC1	NM_015321.3	c.919C>T	p.Arg307Cys	missense_variant	Exon 9 of 14	ENST00000321949.13	NP_056136.2
CRTC1	NM_001098482.2	c.967C>T	p.Arg323Cys	missense_variant	Exon 10 of 15		NP_001091952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTC1	ENST00000321949.13	c.919C>T	p.Arg307Cys	missense_variant	Exon 9 of 14	1	NM_015321.3	ENSP00000323332.7
CRTC1	ENST00000338797.10	c.967C>T	p.Arg323Cys	missense_variant	Exon 10 of 15	1		ENSP00000345001.5
CRTC1	ENST00000594658.5	c.796C>T	p.Arg266Cys	missense_variant	Exon 9 of 14	1		ENSP00000468893.1
CRTC1	ENST00000601916.1	c.694C>T	p.Arg232Cys	missense_variant	Exon 8 of 10	5		ENSP00000469285.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 250544 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135502

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460752 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726710

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000571 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.967C>T (p.R323C) alteration is located in exon 10 (coding exon 10) of the CRTC1 gene. This alteration results from a C to T substitution at nucleotide position 967, causing the arginine (R) at amino acid position 323 to be replaced by a cysteine (C). 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	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;.;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.043
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.6	D;D;.;.
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D;D;.;.
Sift4G	Uncertain	0.040	D;D;D;D
Polyphen		0.98	D;D;.;.
Vest4		0.68
MutPred		0.19		Loss of glycosylation at S303 (P = 0.1092);.;.;.;
MVP		0.38
MPC		1.7
ClinPred		0.87	D
GERP RS		3.1
Varity_R		0.34
gMVP		0.61

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: rs1274858564; hg19: chr19-18876246;