rs587780887

Variant names:

• chr2-130592943-C-G
• rs587780887
• NM_032545.4:c.606G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-130592943-C-G
• chr2-130592943-C-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.491G>C​(p.Trp164Ser) 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 0.014 (4 hom., cov: 7)
  • Exomes 𝑓: 0.0026 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFC1 NM_001270420.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -2.04
• 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=0.0030456483).
• BP6: Variant 2-130592943-C-G is Benign according to our data. Variant chr2-130592943-C-G is described in ClinVar as Benign. ClinVar VariationId is 136738.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.606G>C	p.Leu202Leu	synonymous	Exon 6 of 6	NP_115934.1	P0CG37
	CFC1	NM_001270420.2		c.491G>C	p.Trp164Ser	missense	Exon 5 of 5	NP_001257349.1	A0A087WWV2
	CFC1	NM_001270421.2		c.381G>C	p.Leu127Leu	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.606G>C	p.Leu202Leu	synonymous	Exon 6 of 6	ENSP00000259216.5	P0CG37
	CFC1	ENST00000615342.4	TSL:5	c.491G>C	p.Trp164Ser	missense	Exon 5 of 5	ENSP00000480526.1	A0A087WWV2
	CFC1	ENST00000621673.4	TSL:2	c.381G>C	p.Leu127Leu	synonymous	Exon 4 of 4	ENSP00000480843.1	A0A087WX98

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 777 AN: 57254 Hom.: 4 Cov.: 7

Gnomad AFR AF: 0.0592

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0159

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: 0.000186

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00865 AC: 425 AN: 49118 AF XY: 0.00738

Gnomad AFR exome AF: 0.0801

Gnomad AMR exome AF: 0.00482

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000259

Gnomad OTH exome AF: 0.00348

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00264 AC: 1148 AN: 435194 Hom.: 3 Cov.: 0 AF XY: 0.00224 AC XY: 512 AN XY: 228220

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

African (AFR) AF: 0.0755 AC: 836 AN: 11074

American (AMR) AF: 0.00560 AC: 101 AN: 18046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13544

East Asian (EAS) AF: 0.00 AC: 0 AN: 30304

South Asian (SAS) AF: 0.000115 AC: 5 AN: 43588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28738

Middle Eastern (MID) AF: 0.00365 AC: 7 AN: 1920

European-Non Finnish (NFE) AF: 0.000194 AC: 51 AN: 262636

Other (OTH) AF: 0.00584 AC: 148 AN: 25344

⚠️ 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: 0.0136 AC: 779 AN: 57206 Hom.: 4 Cov.: 7 AF XY: 0.0149 AC XY: 352 AN XY: 23688

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

African (AFR) AF: 0.0592 AC: 691 AN: 11664

American (AMR) AF: 0.0159 AC: 70 AN: 4414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1958

East Asian (EAS) AF: 0.00 AC: 0 AN: 2846

South Asian (SAS) AF: 0.00 AC: 0 AN: 1566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 212

European-Non Finnish (NFE) AF: 0.000186 AC: 6 AN: 32174

Other (OTH) AF: 0.0153 AC: 12 AN: 784

⚠️ 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: 0.0128 Hom.: 1

ExAC AF: 0.000929 AC: 2

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-1.2
CADD	Benign	1.2
DANN	Benign	0.46
FATHMM_MKL	Benign	0.00015	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0030	T
PhyloP100		-2.0
Vest4		0.17
MVP		0.043
GERP RS		-3.3
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: rs587780887; hg19: chr2-131350516;