2-130597533-C-T

Position:

• chr2-130597533-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_032545.4(CFC1):​c.433G>A​(p.Ala145Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.072 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFC1 NM_032545.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.143

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17100677).
• BP6: Variant 2-130597533-C-T is Benign according to our data. Variant chr2-130597533-C-T is described in ClinVar as [Benign]. Clinvar id is 136735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-130597533-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFC1	NM_032545.4	c.433G>A	p.Ala145Thr	missense_variant	5/6	ENST00000259216.6	NP_115934.1
CFC1	NM_001270420.2	c.318G>A	p.Gly106=	synonymous_variant	4/5		NP_001257349.1
CFC1	NM_001270421.2	c.247+1109G>A		intron_variant			NP_001257350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFC1	ENST00000259216.6	c.433G>A	p.Ala145Thr	missense_variant	5/6	1	NM_032545.4	ENSP00000259216	P1
CFC1	ENST00000615342.4	c.318G>A	p.Gly106=	synonymous_variant	4/5	5		ENSP00000480526
CFC1	ENST00000621673.4	c.247+1109G>A		intron_variant		2		ENSP00000480843

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 0 Hom.: 0 Cov.: 0 FAILED QC

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0717 AC: 5279 AN: 73600 Hom.: 5 Cov.: 0 AF XY: 0.0688 AC XY: 2649 AN XY: 38478

Gnomad4 AFR exome AF: 0.0207

Gnomad4 AMR exome AF: 0.0606

Gnomad4 ASJ exome AF: 0.0973

Gnomad4 EAS exome AF: 0.00101

Gnomad4 SAS exome AF: 0.0357

Gnomad4 FIN exome AF: 0.0504

Gnomad4 NFE exome AF: 0.0887

Gnomad4 OTH exome AF: 0.0724

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 0

Gnomad4 AFR AF: 0.00

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0282 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Heterotaxy, visceral, 2, autosomal Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.79
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0052	N
LIST_S2	Benign	0.20	T
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.22
Sift	Benign	0.73	T
Sift4G	Benign	0.62	T
Polyphen		0.0010	B
Vest4		0.13
MPC		1.3
ClinPred		0.00030	T
GERP RS		-0.52
Varity_R		0.031
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs199715380; hg19: chr2-131355106;