2-130598657-G-A

Position:

• chr2-130598657-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_032545.4(CFC1):​c.232C>T​(p.Arg78Trp) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CFC1 NM_032545.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.88

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19209534).
• BP6: Variant 2-130598657-G-A is Benign according to our data. Variant chr2-130598657-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1216095.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFC1	NM_032545.4	c.232C>T	p.Arg78Trp	missense_variant	3/6	ENST00000259216.6	NP_115934.1
CFC1	NM_001270420.2	c.232C>T	p.Arg78Trp	missense_variant	3/5		NP_001257349.1
CFC1	NM_001270421.2	c.232C>T	p.Arg78Trp	missense_variant	3/4		NP_001257350.1
CFC1	XM_011511486.4	c.232C>T	p.Arg78Trp	missense_variant	3/4		XP_011509788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFC1	ENST00000259216.6	c.232C>T	p.Arg78Trp	missense_variant	3/6	1	NM_032545.4	ENSP00000259216	P1
CFC1	ENST00000615342.4	c.232C>T	p.Arg78Trp	missense_variant	3/5	5		ENSP00000480526
CFC1	ENST00000621673.4	c.232C>T	p.Arg78Trp	missense_variant	3/4	2		ENSP00000480843

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 11062482, 17445335) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	0.37
DANN	Benign	0.73
DEOGEN2	Benign	0.12	.;.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.52	T;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.60	.;.;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.4	.;.;N
REVEL	Uncertain	0.51
Sift	Benign	0.23	.;.;T
Sift4G	Uncertain	0.049	D;T;T
Polyphen		0.0	.;.;B
Vest4		0.20
MutPred		0.71		Loss of disorder (P = 0.0042);Loss of disorder (P = 0.0042);Loss of disorder (P = 0.0042);
MVP		0.53
MPC		1.3
ClinPred		0.057	T
GERP RS		-3.8
Varity_R		0.032
gMVP		0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-131356230;