rs776829911

Variant names:

• chr2-130593065-A-G
• rs776829911
• NM_032545.4:c.484T>C

Variant summary

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

The NM_032545.4(CFC1):​c.484T>C​(p.Phe162Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0053 (0 hom., cov: 19)
  • Exomes 𝑓: 0.00087 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFC1 NM_032545.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.235
• Publications: 4 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: G2P, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000296239 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008504361).
• BP6: Variant 2-130593065-A-G is Benign according to our data. Variant chr2-130593065-A-G is described in ClinVar as Benign. ClinVar VariationId is 801752.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032545.4. 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.484T>C	p.Phe162Leu	missense	Exon 6 of 6	NP_115934.1	P0CG37
	CFC1	NM_001270421.2		c.259T>C	p.Phe87Leu	missense	Exon 4 of 4	NP_001257350.1	A0A087WX98
	CFC1	NM_001270420.2		c.369T>C	p.Thr123Thr	synonymous	Exon 5 of 5	NP_001257349.1	A0A087WWV2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFC1	ENST00000259216.6	TSL:1 MANE Select	c.484T>C	p.Phe162Leu	missense	Exon 6 of 6	ENSP00000259216.5	P0CG37
	CFC1	ENST00000621673.4	TSL:2	c.259T>C	p.Phe87Leu	missense	Exon 4 of 4	ENSP00000480843.1	A0A087WX98
	CFC1	ENST00000615342.4	TSL:5	c.369T>C	p.Thr123Thr	synonymous	Exon 5 of 5	ENSP00000480526.1	A0A087WWV2

Frequencies

GnomAD3 genomes AF: 0.00525 AC: 673 AN: 128156 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00285

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: 0.0000486

Gnomad OTH AF: 0.00369

GnomAD2 exomes AF: 0.00256 AC: 141 AN: 55054 AF XY: 0.00208

Gnomad AFR exome AF: 0.0240

Gnomad AMR exome AF: 0.00126

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00103

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000867 AC: 356 AN: 410748 Hom.: 1 Cov.: 0 AF XY: 0.000674 AC XY: 146 AN XY: 216528

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

African (AFR) AF: 0.0231 AC: 251 AN: 10852

American (AMR) AF: 0.00184 AC: 32 AN: 17428

Ashkenazi Jewish (ASJ) AF: 0.0000786 AC: 1 AN: 12720

East Asian (EAS) AF: 0.00 AC: 0 AN: 27978

South Asian (SAS) AF: 0.000135 AC: 6 AN: 44392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25002

Middle Eastern (MID) AF: 0.00110 AC: 2 AN: 1824

European-Non Finnish (NFE) AF: 0.0000851 AC: 21 AN: 246838

Other (OTH) AF: 0.00181 AC: 43 AN: 23714

⚠️ 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: 0.00529 AC: 678 AN: 128270 Hom.: 0 Cov.: 19 AF XY: 0.00490 AC XY: 299 AN XY: 61034

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

African (AFR) AF: 0.0200 AC: 633 AN: 31582

American (AMR) AF: 0.00285 AC: 36 AN: 12636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3254

East Asian (EAS) AF: 0.00 AC: 0 AN: 4492

South Asian (SAS) AF: 0.00 AC: 0 AN: 3410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.0000486 AC: 3 AN: 61772

Other (OTH) AF: 0.00364 AC: 6 AN: 1648

⚠️ 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: 0.00513 Hom.: 0

ExAC AF: 0.000344 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Heterotaxy, visceral, 2, autosomal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	14
DANN	Benign	0.75
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-0.72	T
PhyloP100		0.23
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.61	N
REVEL	Uncertain	0.51
Sift	Benign	0.40	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0080	B
Vest4		0.25
MutPred		0.75		Gain of disorder (P = 0.0994)
MVP		0.93
MPC		1.5
ClinPred		0.0011	T
GERP RS		0.92
Varity_R		0.043
gMVP		0.18
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs776829911; hg19: chr2-131350638;