Genetic Variant CFC1:p.Ser205Ser (chr2-130592934-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001270420.2(CFC1):c.500C>G(p.Pro167Arg) 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 0.0015 ( 0 hom., cov: 7)

Exomes 𝑓: 0.00031 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CFC1
NM_001270420.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.780

Publications

1 publications found

Variant links:

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

CFC1 links:

ENSG00000296239 (HGNC:):

ENSG00000296239 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00693053).

BP6

Variant 2-130592934-G-C is Benign according to our data. Variant chr2-130592934-G-C is described in ClinVar as Benign. ClinVar VariationId is 136739.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CFC1	NM_032545.4	MANE Select	c.615C>G	p.Ser205Ser	synonymous	Exon 6 of 6	NP_115934.1	P0CG37
CFC1	NM_001270420.2		c.500C>G	p.Pro167Arg	missense	Exon 5 of 5	NP_001257349.1	A0A087WWV2
CFC1	NM_001270421.2		c.390C>G	p.Ser130Ser	synonymous	Exon 4 of 4	NP_001257350.1	A0A087WX98

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CFC1	ENST00000259216.6	TSL:1 MANE Select	c.615C>G	p.Ser205Ser	synonymous	Exon 6 of 6	ENSP00000259216.5	P0CG37
CFC1	ENST00000615342.4	TSL:5	c.500C>G	p.Pro167Arg	missense	Exon 5 of 5	ENSP00000480526.1	A0A087WWV2
CFC1	ENST00000621673.4	TSL:2	c.390C>G	p.Ser130Ser	synonymous	Exon 4 of 4	ENSP00000480843.1	A0A087WX98

Frequencies

GnomAD3 genomes

AF:

0.00144

AC:

AN:

55542

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00591

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00166

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:

0.0000324

Gnomad OTH

AF:

0.00132

GnomAD2 exomes

AF:

0.00101

AC:

AN:

45568

AF XY:

0.000730

show subpopulations

Gnomad AFR exome

AF:

0.00824

Gnomad AMR exome

AF:

0.000568

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000109

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000310

AC:

134

AN:

431648

Hom.:

Cov.:

AF XY:

0.000266

AC XY:

AN XY:

225984

show subpopulations

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

African (AFR)

AF:

0.00881

AC:

105

AN:

11924

American (AMR)

AF:

0.000457

AC:

AN:

17520

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13448

East Asian (EAS)

AF:

0.00

AC:

AN:

29874

South Asian (SAS)

AF:

0.00

AC:

AN:

42862

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28494

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1922

European-Non Finnish (NFE)

AF:

0.0000230

AC:

AN:

260330

Other (OTH)

AF:

0.000593

AC:

AN:

25274

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.288

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00146

AC:

AN:

55502

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

AN XY:

22748

show subpopulations

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

African (AFR)

AF:

0.00598

AC:

AN:

12034

American (AMR)

AF:

0.00166

AC:

AN:

4210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1902

East Asian (EAS)

AF:

0.00

AC:

AN:

2758

South Asian (SAS)

AF:

0.00

AC:

AN:

1474

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1004

Middle Eastern (MID)

AF:

0.00

AC:

AN:

196

European-Non Finnish (NFE)

AF:

0.0000325

AC:

AN:

30816

Other (OTH)

AF:

0.00132

AC:

AN:

758

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.348

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00110

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.91

CADD

Benign

2.0

(source)

DANN

Benign

0.60

FATHMM_MKL

Benign

0.0044

LIST_S2

Benign

0.33

MetaRNN

Benign

0.0069

PhyloP100

-0.78

Vest4

0.23

MVP

0.068

GERP RS

-0.12

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over