2-130598920-A-G

Position:

• chr2-130598920-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_032545.4(CFC1):​c.63T>C​(p.Asn21=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (1 hom., cov: 20)
  • Exomes 𝑓: 0.0026 (1 hom.)
• Consequence: CFC1 NM_032545.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.505

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 2-130598920-A-G is Benign according to our data. Variant chr2-130598920-A-G is described in ClinVar as [Benign]. Clinvar id is 136732.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-130598920-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.505 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0852 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFC1	NM_032545.4	c.63T>C	p.Asn21=	synonymous_variant	2/6	ENST00000259216.6
CFC1	NM_001270420.2	c.63T>C	p.Asn21=	synonymous_variant	2/5
CFC1	NM_001270421.2	c.63T>C	p.Asn21=	synonymous_variant	2/4
CFC1	XM_011511486.4	c.63T>C	p.Asn21=	synonymous_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFC1	ENST00000259216.6	c.63T>C	p.Asn21=	synonymous_variant	2/6	1	NM_032545.4	P1
CFC1	ENST00000615342.4	c.63T>C	p.Asn21=	synonymous_variant	2/5	5
CFC1	ENST00000621673.4	c.63T>C	p.Asn21=	synonymous_variant	2/4	2

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 2921 AN: 133926 Hom.: 1 Cov.: 20

Gnomad AFR AF: 0.0879

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000755

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000260

Gnomad OTH AF: 0.0164

GnomAD4 exome AF: 0.00257 AC: 2523 AN: 982112 Hom.: 1 Cov.: 13 AF XY: 0.00214 AC XY: 1062 AN XY: 495346

Gnomad4 AFR exome AF: 0.0964

Gnomad4 AMR exome AF: 0.00567

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000198

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000198

Gnomad4 OTH exome AF: 0.00600

GnomAD4 genome AF: 0.0219 AC: 2931 AN: 134026 Hom.: 1 Cov.: 20 AF XY: 0.0209 AC XY: 1350 AN XY: 64460

Gnomad4 AFR AF: 0.0879

Gnomad4 AMR AF: 0.0117

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000504

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000260

Gnomad4 OTH AF: 0.0162

Alfa AF: 0.0160 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 31, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	4.1
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs200918108; hg19: chr2-131356493;