chr19-18765494-C-T

Variant names:

• chr19-18765494-C-T
• rs756822056
• NM_015321.3:c.977C>T

Variant summary

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

The NM_015321.3(CRTC1):​c.977C>T​(p.Ser326Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,457,544 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: 0.000012 (0 hom.)
• Consequence: CRTC1 NM_015321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.63

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 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC1	NM_015321.3	c.977C>T	p.Ser326Leu	missense_variant	Exon 9 of 14	ENST00000321949.13	NP_056136.2
CRTC1	NM_001098482.2	c.1025C>T	p.Ser342Leu	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.977C>T	p.Ser326Leu	missense_variant	Exon 9 of 14	1	NM_015321.3	ENSP00000323332.7
CRTC1	ENST00000338797.10	c.1025C>T	p.Ser342Leu	missense_variant	Exon 10 of 15	1		ENSP00000345001.5
CRTC1	ENST00000594658.5	c.854C>T	p.Ser285Leu	missense_variant	Exon 9 of 14	1		ENSP00000468893.1
CRTC1	ENST00000601916.1	c.752C>T	p.Ser251Leu	missense_variant	Exon 8 of 10	5		ENSP00000469285.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000808 AC: 2 AN: 247540 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134186

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1457544 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 725278

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1025C>T (p.S342L) 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 1025, causing the serine (S) at amino acid position 342 to be replaced by a leucine (L). 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	0.14
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	T;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;D;T;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.2	D;D;.;.
REVEL	Benign	0.11
Sift	Uncertain	0.0020	D;D;.;.
Sift4G	Benign	0.091	T;T;T;D
Polyphen		0.78	P;D;.;.
Vest4		0.52
MutPred		0.23		Gain of helix (P = 0.0199);.;.;.;
MVP		0.28
MPC		1.2
ClinPred		0.83	D
GERP RS		4.4
Varity_R		0.33
gMVP		0.60

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: rs756822056; hg19: chr19-18876304; COSMIC: COSV58716021;