rs587780888

Variant names:

• chr2-130592934-G-A
• rs587780888
• NM_032545.4:c.615C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-130592934-G-A
• chr2-130592934-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001270420.2(CFC1):​c.500C>T​(p.Pro167Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P167R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 7)
  • Exomes 𝑓: 0.0000069 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFC1 NM_001270420.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.780
• Publications: 0 publications found

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]

CFC1 Gene-Disease associations (from GenCC):

• heterotaxy, visceral, 2, autosomal

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ENSG00000296239 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.088758945).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270420.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFC1	NM_032545.4	MANE Select	c.615C>T	p.Ser205Ser	synonymous	Exon 6 of 6	NP_115934.1	P0CG37
	CFC1	NM_001270420.2		c.500C>T	p.Pro167Leu	missense	Exon 5 of 5	NP_001257349.1	A0A087WWV2
	CFC1	NM_001270421.2		c.390C>T	p.Ser130Ser	synonymous	Exon 4 of 4	NP_001257350.1	A0A087WX98

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFC1	ENST00000259216.6	TSL:1 MANE Select	c.615C>T	p.Ser205Ser	synonymous	Exon 6 of 6	ENSP00000259216.5	P0CG37
	CFC1	ENST00000615342.4	TSL:5	c.500C>T	p.Pro167Leu	missense	Exon 5 of 5	ENSP00000480526.1	A0A087WWV2
	CFC1	ENST00000621673.4	TSL:2	c.390C>T	p.Ser130Ser	synonymous	Exon 4 of 4	ENSP00000480843.1	A0A087WX98

Frequencies

GnomAD3 genomes Cov.: 7

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000695 AC: 3 AN: 431796 Hom.: 0 Cov.: 0 AF XY: 0.00000885 AC XY: 2 AN XY: 226052

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 12048

American (AMR) AF: 0.00 AC: 0 AN: 17532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13448

East Asian (EAS) AF: 0.0000670 AC: 2 AN: 29872

South Asian (SAS) AF: 0.00 AC: 0 AN: 42864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1922

European-Non Finnish (NFE) AF: 0.00000384 AC: 1 AN: 260330

Other (OTH) AF: 0.00 AC: 0 AN: 25286

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 7

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.0
DANN	Benign	0.93
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.089	T
PhyloP100		-0.78
Vest4		0.17
MVP		0.043
GERP RS		-0.12
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs587780888; hg19: chr2-131350507; COSMIC: COSV52090563; COSMIC: COSV52090563;