rs199607550

Positions:

• chr2-130598922-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032545.4(CFC1):​c.61A>C​(p.Asn21His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N21N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.039 (104 hom., cov: 19)
  • Exomes 𝑓: 0.0048 (109 hom.)
• Consequence: CFC1 NM_032545.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.82

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029240549).
• BP6: Variant 2-130598922-T-G is Benign according to our data. Variant chr2-130598922-T-G is described in ClinVar as [Benign]. Clinvar id is 136731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-130598922-T-G is described in Lovd as [Benign]. Variant chr2-130598922-T-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFC1	NM_032545.4	c.61A>C	p.Asn21His	missense_variant	2/6	ENST00000259216.6	NP_115934.1
CFC1	NM_001270420.2	c.61A>C	p.Asn21His	missense_variant	2/5		NP_001257349.1
CFC1	NM_001270421.2	c.61A>C	p.Asn21His	missense_variant	2/4		NP_001257350.1
CFC1	XM_011511486.4	c.61A>C	p.Asn21His	missense_variant	2/4		XP_011509788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFC1	ENST00000259216.6	c.61A>C	p.Asn21His	missense_variant	2/6	1	NM_032545.4	ENSP00000259216.5
CFC1	ENST00000615342.4	c.61A>C	p.Asn21His	missense_variant	2/5	5		ENSP00000480526.1
CFC1	ENST00000621673.4	c.61A>C	p.Asn21His	missense_variant	2/4	2		ENSP00000480843.1

Frequencies

GnomAD3 genomes AF: 0.0393 AC: 5193 AN: 132174 Hom.: 103 Cov.: 19

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0210

Gnomad ASJ AF: 0.00420

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00232

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0192

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0125 AC: 1535 AN: 122496 Hom.: 46 AF XY: 0.0106 AC XY: 692 AN XY: 64980

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.00380

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000648

Gnomad FIN exome AF: 0.0000730

Gnomad NFE exome AF: 0.000833

Gnomad OTH exome AF: 0.00793

GnomAD4 exome AF: 0.00480 AC: 4645 AN: 967394 Hom.: 109 Cov.: 13 AF XY: 0.00409 AC XY: 1997 AN XY: 488434

Gnomad4 AFR exome AF: 0.171

Gnomad4 AMR exome AF: 0.0111

Gnomad4 ASJ exome AF: 0.00377

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000340

Gnomad4 FIN exome AF: 0.000172

Gnomad4 NFE exome AF: 0.000465

Gnomad4 OTH exome AF: 0.0127

GnomAD4 genome AF: 0.0394 AC: 5208 AN: 132268 Hom.: 104 Cov.: 19 AF XY: 0.0376 AC XY: 2389 AN XY: 63478

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.0209

Gnomad4 ASJ AF: 0.00420

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00181

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000646

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0213 Hom.: 10

ExAC AF: 0.00666 AC: 656

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 22, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2013	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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.0
DANN	Benign	0.20
DEOGEN2	Benign	0.10	.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00092	N
LIST_S2	Benign	0.42	T;T;T
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-2.1	.;.;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.3	.;.;N
REVEL	Benign	0.16
Sift	Benign	0.72	.;.;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.15
MPC		1.3
ClinPred		0.0061	T
GERP RS		0.97
Varity_R		0.036
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199607550; hg19: chr2-131356495; COSMIC: COSV52090978; COSMIC: COSV52090978;