2-130598922-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032545.4(CFC1):c.61A>C(p.Asn21His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N21N) has been classified as Benign.

Frequency

Genomes: 𝑓 0.039 ( 104 hom., cov: 19)

Exomes 𝑓: 0.0048 ( 109 hom. )

Consequence

CFC1
NM_032545.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.82

Publications

5 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: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

CFC1 links:

ENSG00000296255 (HGNC:):

ENSG00000296255 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029240549).

BP6

Variant 2-130598922-T-G is Benign according to our data. Variant chr2-130598922-T-G is described in ClinVar as Benign. ClinVar VariationId is 136731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFC1	NM_032545.4 link	c.61A>C	p.Asn21His	missense_variant	Exon 2 of 6	ENST00000259216.6	NP_115934.1	P0CG37
CFC1	NM_001270420.2 link	c.61A>C	p.Asn21His	missense_variant	Exon 2 of 5		NP_001257349.1	P0CG37A0A087WWV2
CFC1	NM_001270421.2 link	c.61A>C	p.Asn21His	missense_variant	Exon 2 of 4		NP_001257350.1	P0CG37A0A087WX98
CFC1	XM_011511486.4 link	c.61A>C	p.Asn21His	missense_variant	Exon 2 of 4		XP_011509788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFC1	ENST00000259216.6 link	c.61A>C	p.Asn21His	missense_variant	Exon 2 of 6	1	NM_032545.4	ENSP00000259216.5		P0CG37

Frequencies

GnomAD3 genomes

AF:

0.0393

AC:

5193

AN:

132174

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0210

Gnomad ASJ

AF:

0.00420

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00232

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0192

Gnomad NFE

AF:

0.000661

Gnomad OTH

AF:

0.0301

GnomAD2 exomes

AF:

0.0125

AC:

1535

AN:

122496

AF XY:

0.0106

show subpopulations

Gnomad AFR exome

AF:

0.193

Gnomad AMR exome

AF:

0.0102

Gnomad ASJ exome

AF:

0.00380

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000730

Gnomad NFE exome

AF:

0.000833

Gnomad OTH exome

AF:

0.00793

GnomAD4 exome

AF:

0.00480

AC:

4645

AN:

967394

Hom.:

109

Cov.:

AF XY:

0.00409

AC XY:

1997

AN XY:

488434

show subpopulations

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

African (AFR)

AF:

0.171

AC:

3287

AN:

19248

American (AMR)

AF:

0.0111

AC:

348

AN:

31420

Ashkenazi Jewish (ASJ)

AF:

0.00377

AC:

AN:

20672

East Asian (EAS)

AF:

0.00

AC:

AN:

33614

South Asian (SAS)

AF:

0.000340

AC:

AN:

64728

European-Finnish (FIN)

AF:

0.000172

AC:

AN:

46576

Middle Eastern (MID)

AF:

0.00928

AC:

AN:

3124

European-Non Finnish (NFE)

AF:

0.000465

AC:

328

AN:

704990

Other (OTH)

AF:

0.0127

AC:

545

AN:

43022

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.384

Heterozygous variant carriers

214

428

641

855

1069

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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

AF:

0.0394

AC:

5208

AN:

132268

Hom.:

104

Cov.:

AF XY:

0.0376

AC XY:

2389

AN XY:

63478

show subpopulations

African (AFR)

AF:

0.159

AC:

4813

AN:

30176

American (AMR)

AF:

0.0209

AC:

274

AN:

13098

Ashkenazi Jewish (ASJ)

AF:

0.00420

AC:

AN:

3334

East Asian (EAS)

AF:

0.00

AC:

AN:

4898

South Asian (SAS)

AF:

0.00181

AC:

AN:

3876

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8954

Middle Eastern (MID)

AF:

0.0241

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000646

AC:

AN:

65054

Other (OTH)

AF:

0.0298

AC:

AN:

1712

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.404

Heterozygous variant carriers

184

368

553

737

921

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.0213

Hom.:

ExAC

AF:

0.00666

AC:

656

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 22, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Aug 07, 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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

7.0

(source)

DANN

Benign

0.20

DEOGEN2

Benign

0.10

.;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.00092

LIST_S2

Benign

0.42

T;T;T

MetaRNN

Benign

0.0029

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-2.1

.;.;N

PhyloP100

1.8

PrimateAI

Benign

0.40

PROVEAN

Benign

1.3

.;.;N

REVEL

Benign

0.16

Sift

Benign

0.72

.;.;T

Sift4G

Benign

0.42

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.15

MPC

1.3

ClinPred

0.0061

GERP RS

0.97

Varity_R

0.036

gMVP

0.12

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over