2-130598675-C-T

Position:

• chr2-130598675-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032545.4(CFC1):​c.214G>A​(p.Glu72Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFC1 NM_032545.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.437

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08917165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFC1	NM_032545.4	c.214G>A	p.Glu72Lys	missense_variant	3/6	ENST00000259216.6	NP_115934.1
CFC1	NM_001270420.2	c.214G>A	p.Glu72Lys	missense_variant	3/5		NP_001257349.1
CFC1	NM_001270421.2	c.214G>A	p.Glu72Lys	missense_variant	3/4		NP_001257350.1
CFC1	XM_011511486.4	c.214G>A	p.Glu72Lys	missense_variant	3/4		XP_011509788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFC1	ENST00000259216.6	c.214G>A	p.Glu72Lys	missense_variant	3/6	1	NM_032545.4	ENSP00000259216	P1
CFC1	ENST00000615342.4	c.214G>A	p.Glu72Lys	missense_variant	3/5	5		ENSP00000480526
CFC1	ENST00000621673.4	c.214G>A	p.Glu72Lys	missense_variant	3/4	2		ENSP00000480843

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1461626 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727124

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 22

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

Apr 06, 2022

The c.214G>A (p.E72K) 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 214, causing the glutamic acid (E) at amino acid position 72 to be replaced by a lysine (K). 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	0.095
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	.;.;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.089	T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.1	.;.;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.98	.;.;N
REVEL	Benign	0.18
Sift	Benign	0.29	.;.;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.28	.;.;B
Vest4		0.16
MutPred		0.32		Gain of ubiquitination at E72 (P = 0.0075);Gain of ubiquitination at E72 (P = 0.0075);Gain of ubiquitination at E72 (P = 0.0075);
MVP		0.10
MPC		1.5
ClinPred		0.17	T
GERP RS		1.7
Varity_R		0.068
gMVP		0.15

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: rs1258754067; hg19: chr2-131356248; COSMIC: COSV52090547; COSMIC: COSV52090547;