2-130593026-CG-C

Position:

• chr2-130593026-CG-C

Variant summary

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

The NM_032545.4(CFC1):​c.522del​(p.Ala175ArgfsTer56) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., cov: 14)
  • Exomes 𝑓: 0.0015 (0 hom.)
• Consequence: CFC1 NM_032545.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:1
• Conservation: PhyloP100: 0.0630

Genes affected

CFC1 (HGNC:18292): (cryptic, EGF-CFC family member 1) This gene encodes a member of the epidermal growth factor (EGF)- Cripto, Frl-1, and Cryptic (CFC) family, which are involved in signalling during embryonic development. Proteins in this family share a variant EGF-like motif, a conserved cysteine-rich domain, and a C-terminal hydrophobic region. The protein encoded by this gene is necessary for patterning the left-right embryonic axis. Mutations in this gene are associated with defects in organ development, including autosomal visceral heterotaxy and congenital heart disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 94 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFC1	NM_032545.4	c.522del	p.Ala175ArgfsTer56	frameshift_variant	6/6	ENST00000259216.6	NP_115934.1
CFC1	NM_001270420.2	c.407del	p.Ala136GlyfsTer61	frameshift_variant	5/5		NP_001257349.1
CFC1	NM_001270421.2	c.297del	p.Ala100ArgfsTer56	frameshift_variant	4/4		NP_001257350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFC1	ENST00000259216.6	c.522del	p.Ala175ArgfsTer56	frameshift_variant	6/6	1	NM_032545.4	ENSP00000259216	P1
CFC1	ENST00000615342.4	c.407del	p.Ala136GlyfsTer61	frameshift_variant	5/5	5		ENSP00000480526
CFC1	ENST00000621673.4	c.297del	p.Ala100ArgfsTer56	frameshift_variant	4/4	2		ENSP00000480843

Frequencies

GnomAD3 genomes AF: 0.000885 AC: 94 AN: 106242 Hom.: 0 Cov.: 14

Gnomad AFR AF: 0.000271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00123

Gnomad ASJ AF: 0.00103

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00230

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00694

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00151 AC: 669 AN: 443488 Hom.: 0 Cov.: 0 AF XY: 0.00165 AC XY: 386 AN XY: 233326

Gnomad4 AFR exome AF: 0.000412

Gnomad4 AMR exome AF: 0.000866

Gnomad4 ASJ exome AF: 0.00397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00308

Gnomad4 FIN exome AF: 0.0000696

Gnomad4 NFE exome AF: 0.00146

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.000884 AC: 94 AN: 106308 Hom.: 0 Cov.: 14 AF XY: 0.000922 AC XY: 45 AN XY: 48824

Gnomad4 AFR AF: 0.000271

Gnomad4 AMR AF: 0.00123

Gnomad4 ASJ AF: 0.00103

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00231

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000298 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Heterotaxy, visceral, 2, autosomal Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2002	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	CFC1: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2023	Also identified in a patient with isolated double-outlet right ventricle and inherited from an asymptomatic parent in the published literature (Goldmuntz et al., 2002); Observed in two unrelated patients with various laterality defects in published literature; one patient inherited the variant from an asymptomatic parent in addition to also having a variant in another heterotaxy-related gene (Bamford et al., 2000); Published in vitro functional studies in zebrafish demonstrate a damaging effect, as the c.522delC mutant was found to be absent from the cell surface and was unable to rescue MZoep mutant phenotype (Bamford et al., 2000); Frameshift variant predicted to result in protein truncation, as the last 49 amino acids are replaced with 55 different amino acids; This variant is associated with the following publications: (PMID: 11062482, 30293987, 31589614, 11799476, Maaged2022[Review]) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs746231039; hg19: chr2-131350599;