2-130592949-C-A

Variant names:

• chr2-130592949-C-A
• rs587780886
• NM_032545.4:c.600G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001270420.2(CFC1):​c.485G>T​(p.Gly162Val) 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. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 8)
  • Exomes 𝑓: 0.00043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFC1 NM_001270420.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.212
• Publications: 1 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006155789).
• BP6: Variant 2-130592949-C-A is Benign according to our data. Variant chr2-130592949-C-A is described in ClinVar as Benign. ClinVar VariationId is 136737.Status of the report is criteria_provided_single_submitter, 1 stars.

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.600G>T	p.Arg200Arg	synonymous	Exon 6 of 6	NP_115934.1	P0CG37
	CFC1	NM_001270420.2		c.485G>T	p.Gly162Val	missense	Exon 5 of 5	NP_001257349.1	A0A087WWV2
	CFC1	NM_001270421.2		c.375G>T	p.Arg125Arg	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.600G>T	p.Arg200Arg	synonymous	Exon 6 of 6	ENSP00000259216.5	P0CG37
	CFC1	ENST00000615342.4	TSL:5	c.485G>T	p.Gly162Val	missense	Exon 5 of 5	ENSP00000480526.1	A0A087WWV2
	CFC1	ENST00000621673.4	TSL:2	c.375G>T	p.Arg125Arg	synonymous	Exon 4 of 4	ENSP00000480843.1	A0A087WX98

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 145 AN: 60230 Hom.: 0 Cov.: 8

Gnomad AFR AF: 0.00990

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000605

Gnomad OTH AF: 0.00367

GnomAD2 exomes AF: 0.00146 AC: 73 AN: 50170 AF XY: 0.00106

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.000569

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000430 AC: 188 AN: 437414 Hom.: 0 Cov.: 0 AF XY: 0.000323 AC XY: 74 AN XY: 229226

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

African (AFR) AF: 0.0122 AC: 147 AN: 12056

American (AMR) AF: 0.000547 AC: 10 AN: 18286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13556

East Asian (EAS) AF: 0.00 AC: 0 AN: 30396

South Asian (SAS) AF: 0.00 AC: 0 AN: 43674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28824

Middle Eastern (MID) AF: 0.000519 AC: 1 AN: 1928

European-Non Finnish (NFE) AF: 0.0000304 AC: 8 AN: 263130

Other (OTH) AF: 0.000861 AC: 22 AN: 25564

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00239 AC: 144 AN: 60186 Hom.: 0 Cov.: 8 AF XY: 0.00260 AC XY: 65 AN XY: 24994

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

African (AFR) AF: 0.00980 AC: 129 AN: 13158

American (AMR) AF: 0.00216 AC: 10 AN: 4636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2006

East Asian (EAS) AF: 0.00 AC: 0 AN: 2924

South Asian (SAS) AF: 0.00 AC: 0 AN: 1628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.0000606 AC: 2 AN: 33030

Other (OTH) AF: 0.00366 AC: 3 AN: 820

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00253 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.1
DANN	Benign	0.68
FATHMM_MKL	Benign	0.0060	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0062	T
PhyloP100		-0.21
Vest4		0.15
MVP		0.068
GERP RS		-1.7
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: rs587780886; hg19: chr2-131350522;