rs104893611

Variant names:

• chr2-130597896-G-A
• rs104893611
• NM_032545.4:c.334C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3_Strong PP5

The NM_032545.4(CFC1):​c.334C>T​(p.Arg112Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 0)
• Consequence: CFC1 NM_032545.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.750
• Publications: 3 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)

ENSG00000296255 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 2-130597896-G-A is Pathogenic according to our data. Variant chr2-130597896-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 5187.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFC1	NM_032545.4	MANE Select	c.334C>T	p.Arg112Cys	missense	Exon 4 of 6	NP_115934.1
	CFC1	NM_001270420.2		c.248-293C>T		intron	N/A	NP_001257349.1
	CFC1	NM_001270421.2		c.247+746C>T		intron	N/A	NP_001257350.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFC1	ENST00000259216.6	TSL:1 MANE Select	c.334C>T	p.Arg112Cys	missense	Exon 4 of 6	ENSP00000259216.5
	CFC1	ENST00000615342.4	TSL:5	c.248-293C>T		intron	N/A	ENSP00000480526.1
	CFC1	ENST00000621673.4	TSL:2	c.247+746C>T		intron	N/A	ENSP00000480843.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Heterotaxy, visceral, 2, autosomal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		0.75
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.90		Loss of disorder (P = 0.0662)
MVP		0.76
MPC		2.9
ClinPred		1.0	D
GERP RS		1.9
Varity_R		0.71
gMVP		0.30
Mutation Taster		=21/79	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104893611; hg19: chr2-131355469;