rs746231039

Variant names:

• chr2-130593026-CG-C
• rs746231039
• NM_032545.4:c.522delC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_032545.4(CFC1):​c.522delC​(p.Ala175ArgfsTer56) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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
• Publications: 1 publications found

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]

CFC1 Gene-Disease associations (from GenCC):

• heterotaxy, visceral, 2, autosomal

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000296239 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 2-130593026-CG-C is Benign according to our data. Variant chr2-130593026-CG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5188.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032545.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFC1	NM_032545.4	MANE Select	c.522delC	p.Ala175ArgfsTer56	frameshift	Exon 6 of 6	NP_115934.1
	CFC1	NM_001270420.2		c.407delC	p.Ala136GlyfsTer61	frameshift	Exon 5 of 5	NP_001257349.1
	CFC1	NM_001270421.2		c.297delC	p.Ala100ArgfsTer56	frameshift	Exon 4 of 4	NP_001257350.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFC1	ENST00000259216.6	TSL:1 MANE Select	c.522delC	p.Ala175ArgfsTer56	frameshift	Exon 6 of 6	ENSP00000259216.5
	CFC1	ENST00000615342.4	TSL:5	c.407delC	p.Ala136GlyfsTer61	frameshift	Exon 5 of 5	ENSP00000480526.1
	CFC1	ENST00000621673.4	TSL:2	c.297delC	p.Ala100ArgfsTer56	frameshift	Exon 4 of 4	ENSP00000480843.1

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

GnomAD2 exomes AF: 0.00127 AC: 68 AN: 53658 AF XY: 0.00114

Gnomad AFR exome AF: 0.000192

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00344

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00172

Gnomad OTH exome AF: 0.00210

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000412 AC: 5 AN: 12136

American (AMR) AF: 0.000866 AC: 16 AN: 18480

Ashkenazi Jewish (ASJ) AF: 0.00397 AC: 54 AN: 13592

East Asian (EAS) AF: 0.00 AC: 0 AN: 30650

South Asian (SAS) AF: 0.00308 AC: 137 AN: 44536

European-Finnish (FIN) AF: 0.0000696 AC: 2 AN: 28716

Middle Eastern (MID) AF: 0.00206 AC: 4 AN: 1944

European-Non Finnish (NFE) AF: 0.00146 AC: 392 AN: 267742

Other (OTH) AF: 0.00230 AC: 59 AN: 25692

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000271 AC: 7 AN: 25876

American (AMR) AF: 0.00123 AC: 12 AN: 9758

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 3 AN: 2904

East Asian (EAS) AF: 0.00 AC: 0 AN: 3942

South Asian (SAS) AF: 0.00231 AC: 6 AN: 2592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5986

Middle Eastern (MID) AF: 0.00752 AC: 2 AN: 266

European-Non Finnish (NFE) AF: 0.00121 AC: 64 AN: 52958

Other (OTH) AF: 0.00 AC: 0 AN: 1314

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000298 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Heterotaxy, visceral, 2, autosomal (2)
-	1	1	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.063
Mutation Taster		=113/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs746231039; hg19: chr2-131350599;