2-130598792-C-T

Position:

• chr2-130598792-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_032545.4(CFC1):​c.97G>A​(p.Gly33Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000332 in 150,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 21)
  • Exomes 𝑓: 0.000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFC1 NM_032545.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.853

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12674212).
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFC1	NM_032545.4	c.97G>A	p.Gly33Ser	missense_variant	3/6	ENST00000259216.6	NP_115934.1
CFC1	NM_001270420.2	c.97G>A	p.Gly33Ser	missense_variant	3/5		NP_001257349.1
CFC1	NM_001270421.2	c.97G>A	p.Gly33Ser	missense_variant	3/4		NP_001257350.1
CFC1	XM_011511486.4	c.97G>A	p.Gly33Ser	missense_variant	3/4		XP_011509788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFC1	ENST00000259216.6	c.97G>A	p.Gly33Ser	missense_variant	3/6	1	NM_032545.4	ENSP00000259216.5
CFC1	ENST00000615342.4	c.97G>A	p.Gly33Ser	missense_variant	3/5	5		ENSP00000480526.1
CFC1	ENST00000621673.4	c.97G>A	p.Gly33Ser	missense_variant	3/4	2		ENSP00000480843.1

Frequencies

GnomAD3 genomes AF: 0.0000332 AC: 5 AN: 150750 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.000481

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000158 AC: 23 AN: 1456780 Hom.: 0 Cov.: 29 AF XY: 0.0000124 AC XY: 9 AN XY: 724788

Gnomad4 AFR exome AF: 0.0000608

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000332 AC: 5 AN: 150750 Hom.: 0 Cov.: 21 AF XY: 0.0000136 AC XY: 1 AN XY: 73550

Gnomad4 AFR AF: 0.0000247

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000443

Gnomad4 OTH AF: 0.000481

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2024

The c.97G>A (p.G33S) alteration is located in exon 3 (coding exon 3) of the CFC1 gene. This alteration results from a G to A substitution at nucleotide position 97, causing the glycine (G) at amino acid position 33 to be replaced by a serine (S). 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	0.088
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	5.0
DANN	Benign	0.87
DEOGEN2	Benign	0.22	.;.;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0044	N
LIST_S2	Benign	0.56	T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.4	.;.;L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	.;.;N
REVEL	Uncertain	0.31
Sift	Benign	0.090	.;.;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.94	.;.;P
Vest4		0.17
MutPred		0.085		Gain of phosphorylation at G33 (P = 0.0652);Gain of phosphorylation at G33 (P = 0.0652);Gain of phosphorylation at G33 (P = 0.0652);
MVP		0.093
MPC		1.6
ClinPred		0.072	T
GERP RS		-0.51
Varity_R		0.062
gMVP		0.16

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: rs777507203; hg19: chr2-131356365;