rs1256990265

Variant names:

• chr2-130593026-C-T
• rs1256990265
• NM_032545.4:c.523G>A

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.523G>A​(p.Ala175Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 14)
  • Exomes 𝑓: 0.0019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFC1 NM_032545.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.51
• Publications: 0 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=0.0071367323).
• BP6: Variant 2-130593026-C-T is Benign according to our data. Variant chr2-130593026-C-T is described in ClinVar as Benign. ClinVar VariationId is 3388902.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.523G>A	p.Ala175Thr	missense	Exon 6 of 6	NP_115934.1	P0CG37
	CFC1	NM_001270421.2		c.298G>A	p.Ala100Thr	missense	Exon 4 of 4	NP_001257350.1	A0A087WX98
	CFC1	NM_001270420.2		c.408G>A	p.Ala136Ala	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.523G>A	p.Ala175Thr	missense	Exon 6 of 6	ENSP00000259216.5	P0CG37
	CFC1	ENST00000621673.4	TSL:2	c.298G>A	p.Ala100Thr	missense	Exon 4 of 4	ENSP00000480843.1	A0A087WX98
	CFC1	ENST00000615342.4	TSL:5	c.408G>A	p.Ala136Ala	synonymous	Exon 5 of 5	ENSP00000480526.1	A0A087WWV2

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 137 AN: 106250 Hom.: 0 Cov.: 14

Gnomad AFR AF: 0.0000776

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000688

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00839

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.00307

GnomAD2 exomes AF: 0.00119 AC: 64 AN: 53658 AF XY: 0.00144

Gnomad AFR exome AF: 0.000192

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.000688

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0100

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.00105

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00193 AC: 857 AN: 443434 Hom.: 0 Cov.: 0 AF XY: 0.00189 AC XY: 441 AN XY: 233390

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

African (AFR) AF: 0.000247 AC: 3 AN: 12138

American (AMR) AF: 0.00200 AC: 37 AN: 18478

Ashkenazi Jewish (ASJ) AF: 0.000441 AC: 6 AN: 13608

East Asian (EAS) AF: 0.00 AC: 0 AN: 30650

South Asian (SAS) AF: 0.000246 AC: 11 AN: 44634

European-Finnish (FIN) AF: 0.00910 AC: 260 AN: 28562

Middle Eastern (MID) AF: 0.000512 AC: 1 AN: 1954

European-Non Finnish (NFE) AF: 0.00185 AC: 495 AN: 267722

Other (OTH) AF: 0.00171 AC: 44 AN: 25688

⚠️ 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: 0.00129 AC: 137 AN: 106316 Hom.: 0 Cov.: 14 AF XY: 0.00154 AC XY: 75 AN XY: 48836

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

African (AFR) AF: 0.0000773 AC: 2 AN: 25876

American (AMR) AF: 0.00164 AC: 16 AN: 9762

Ashkenazi Jewish (ASJ) AF: 0.000688 AC: 2 AN: 2906

East Asian (EAS) AF: 0.00 AC: 0 AN: 3942

South Asian (SAS) AF: 0.00 AC: 0 AN: 2592

European-Finnish (FIN) AF: 0.00839 AC: 50 AN: 5960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.00119 AC: 63 AN: 52984

Other (OTH) AF: 0.00304 AC: 4 AN: 1314

⚠️ 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: 0.000727 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.1
DANN	Uncertain	0.98
DEOGEN2	Benign	0.095	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00055	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.55	T
PhyloP100		-2.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.55	N
REVEL	Benign	0.17
Sift	Benign	0.60	T
Sift4G	Benign	0.30	T
Polyphen		0.010	B
Vest4		0.13
MVP		0.068
MPC		2.3
ClinPred		0.026	T
GERP RS		-2.7
Varity_R		0.023
gMVP		0.15
Mutation Taster		=99/1	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: rs1256990265; hg19: chr2-131350599;