16-30902524-C-G

Position:

• chr16-30902524-C-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001330.5(CTF1):​c.591C>G​(p.Pro197=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,496,536 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P197P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (3 hom.)
• Consequence: CTF1 NM_001330.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.188

Genes affected

CTF1 (HGNC:2499): (cardiotrophin 1) The protein encoded by this gene is a secreted cytokine that induces cardiac myocyte hypertrophy in vitro. It has been shown to bind and activate the ILST/gp130 receoptor. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 16-30902524-C-G is Benign according to our data. Variant chr16-30902524-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 44182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.188 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTF1	NM_001330.5	c.591C>G	p.Pro197=	synonymous_variant	3/3	ENST00000279804.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTF1	ENST00000279804.3	c.591C>G	p.Pro197=	synonymous_variant	3/3	1	NM_001330.5	P3
CTF1	ENST00000395019.3	c.588C>G	p.Pro196=	synonymous_variant	3/3	1		A1

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 232 AN: 152046 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00202

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00208 AC: 214 AN: 103072 Hom.: 0 AF XY: 0.00204 AC XY: 119 AN XY: 58380

Gnomad AFR exome AF: 0.000766

Gnomad AMR exome AF: 0.00443

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00268

Gnomad OTH exome AF: 0.00234

GnomAD4 exome AF: 0.00213 AC: 2866 AN: 1344380 Hom.: 3 Cov.: 30 AF XY: 0.00212 AC XY: 1402 AN XY: 662670

Gnomad4 AFR exome AF: 0.000432

Gnomad4 AMR exome AF: 0.00436

Gnomad4 ASJ exome AF: 0.00105

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000131

Gnomad4 FIN exome AF: 0.000242

Gnomad4 NFE exome AF: 0.00242

Gnomad4 OTH exome AF: 0.00194

GnomAD4 genome AF: 0.00152 AC: 232 AN: 152156 Hom.: 0 Cov.: 31 AF XY: 0.00153 AC XY: 114 AN XY: 74386

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00202

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000986 Hom.: 1

Bravo AF: 0.00182

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 22, 2014	p.Pro197Pro in exon 3 of CTF1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.9% (28/3168) of Eur opean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadin stitute.org; dbSNP rs397516652) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 15, 2018	Variant summary: CTF1 c.591C>G results in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0018 in 131558 control chromosomes (gnomAD). The observed variant frequency is approximately 72-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in CTF1 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.591C>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant once as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 04, 2017

- -

Dilated Cardiomyopathy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.6
DANN	Benign	0.75

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: rs397516652; hg19: chr16-30913845;