rs199607550

Variant names:

• chr2-130598922-T-G
• rs199607550
• NM_032545.4:c.61A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.82
• Publications: 5 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

ENSG00000296255 (HGNC:):

ACMG classification

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.

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.61A>C	p.Asn21His	missense	Exon 2 of 6	NP_115934.1	P0CG37
	CFC1	NM_001270420.2		c.61A>C	p.Asn21His	missense	Exon 2 of 5	NP_001257349.1	A0A087WWV2
	CFC1	NM_001270421.2		c.61A>C	p.Asn21His	missense	Exon 2 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.61A>C	p.Asn21His	missense	Exon 2 of 6	ENSP00000259216.5	P0CG37
	CFC1	ENST00000615342.4	TSL:5	c.61A>C	p.Asn21His	missense	Exon 2 of 5	ENSP00000480526.1	A0A087WWV2
	CFC1	ENST00000621673.4	TSL:2	c.61A>C	p.Asn21His	missense	Exon 2 of 4	ENSP00000480843.1	A0A087WX98

Frequencies

GnomAD3 genomes AF: 0.0393 AC: 5193 AN: 132174 Hom.: 103 Cov.: 19

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

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.: 13 AF XY: 0.00409 AC XY: 1997 AN XY: 488434

⚠️ 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: 78 AN: 20672

East Asian (EAS) AF: 0.00 AC: 0 AN: 33614

South Asian (SAS) AF: 0.000340 AC: 22 AN: 64728

European-Finnish (FIN) AF: 0.000172 AC: 8 AN: 46576

Middle Eastern (MID) AF: 0.00928 AC: 29 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), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0394 AC: 5208 AN: 132268 Hom.: 104 Cov.: 19 AF XY: 0.0376 AC XY: 2389 AN XY: 63478

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: 14 AN: 3334

East Asian (EAS) AF: 0.00 AC: 0 AN: 4898

South Asian (SAS) AF: 0.00181 AC: 7 AN: 3876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8954

Middle Eastern (MID) AF: 0.0241 AC: 7 AN: 290

European-Non Finnish (NFE) AF: 0.000646 AC: 42 AN: 65054

Other (OTH) AF: 0.0298 AC: 51 AN: 1712

Alfa AF: 0.0213 Hom.: 10

ExAC AF: 0.00666 AC: 656

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.0
DANN	Benign	0.20
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00092	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-2.1	N
PhyloP100		1.8
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.16
Sift	Benign	0.72	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.15
MPC		1.3
ClinPred		0.0061	T
GERP RS		0.97
Varity_R		0.036
gMVP		0.12
Mutation Taster		=98/2	polymorphism (auto)

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: rs199607550; hg19: chr2-131356495; COSMIC: COSV52090978; COSMIC: COSV52090978;