chr2-130592961-G-T

Variant names:

• chr2-130592961-G-T
• rs587780885
• NM_032545.4:c.588C>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Strong BP6_Moderate

The NM_001270420.2(CFC1):​c.473C>A​(p.Pro158Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 8/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.034 (31 hom., cov: 8)
  • Exomes 𝑓: 0.0073 (27 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFC1 NM_001270420.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -6.16

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 -4 ACMG points.

• PM1: In a lipid_moiety_binding_region GPI-anchor amidated aspartate (size 0) in uniprot entity CFC1_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0023072362).
• BP6: Variant 2-130592961-G-T is Benign according to our data. Variant chr2-130592961-G-T is described in ClinVar as [Benign]. Clinvar id is 136736.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-130592961-G-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFC1	NM_032545.4	c.588C>A	p.Pro196Pro	synonymous_variant	Exon 6 of 6	ENST00000259216.6	NP_115934.1
CFC1	NM_001270420.2	c.473C>A	p.Pro158Gln	missense_variant	Exon 5 of 5		NP_001257349.1
CFC1	NM_001270421.2	c.363C>A	p.Pro121Pro	synonymous_variant	Exon 4 of 4		NP_001257350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFC1	ENST00000259216.6	c.588C>A	p.Pro196Pro	synonymous_variant	Exon 6 of 6	1	NM_032545.4	ENSP00000259216.5
CFC1	ENST00000615342.4	c.473C>A	p.Pro158Gln	missense_variant	Exon 5 of 5	5		ENSP00000480526.1
CFC1	ENST00000621673.4	c.363C>A	p.Pro121Pro	synonymous_variant	Exon 4 of 4	2		ENSP00000480843.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2182 AN: 63360 Hom.: 31 Cov.: 8 FAILED QC

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.00431

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0210

Gnomad NFE AF: 0.000427

Gnomad OTH AF: 0.0456

GnomAD3 exomes AF: 0.0222 AC: 1106 AN: 49756 Hom.: 17 AF XY: 0.0188 AC XY: 474 AN XY: 25264

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.00504

Gnomad EAS exome AF: 0.000135

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00852

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00729 AC: 3179 AN: 436368 Hom.: 27 Cov.: 0 AF XY: 0.00607 AC XY: 1387 AN XY: 228514

Gnomad4 AFR exome AF: 0.190

Gnomad4 AMR exome AF: 0.0150

Gnomad4 ASJ exome AF: 0.00465

Gnomad4 EAS exome AF: 0.0000328

Gnomad4 SAS exome AF: 0.000366

Gnomad4 FIN exome AF: 0.000242

Gnomad4 NFE exome AF: 0.000826

Gnomad4 OTH exome AF: 0.0163

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0344 AC: 2178 AN: 63326 Hom.: 31 Cov.: 8 AF XY: 0.0365 AC XY: 968 AN XY: 26526

Gnomad4 AFR AF: 0.151

Gnomad4 AMR AF: 0.0277

Gnomad4 ASJ AF: 0.00431

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000427

Gnomad4 OTH AF: 0.0452

Alfa AF: 0.00700 Hom.: 3

ExAC AF: 0.000387 AC: 1

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

Jan 16, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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_addAF	Benign	-1.0	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	5.0
DANN	Benign	0.67
FATHMM_MKL	Benign	0.00029	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0023	T
Vest4		0.14
GERP RS		-3.1

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: rs587780885; hg19: chr2-131350534;