2-130598797-T-C

Position:

• chr2-130598797-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_032545.4(CFC1):​c.92A>G​(p.His31Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 150,862 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 21)
  • Exomes 𝑓: 0.00016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFC1 NM_032545.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.228

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.044029146).
• BS2: High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFC1	NM_032545.4	c.92A>G	p.His31Arg	missense_variant	3/6	ENST00000259216.6	NP_115934.1
CFC1	NM_001270420.2	c.92A>G	p.His31Arg	missense_variant	3/5		NP_001257349.1
CFC1	NM_001270421.2	c.92A>G	p.His31Arg	missense_variant	3/4		NP_001257350.1
CFC1	XM_011511486.4	c.92A>G	p.His31Arg	missense_variant	3/4		XP_011509788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFC1	ENST00000259216.6	c.92A>G	p.His31Arg	missense_variant	3/6	1	NM_032545.4	ENSP00000259216	P1
CFC1	ENST00000615342.4	c.92A>G	p.His31Arg	missense_variant	3/5	5		ENSP00000480526
CFC1	ENST00000621673.4	c.92A>G	p.His31Arg	missense_variant	3/4	2		ENSP00000480843

Frequencies

GnomAD3 genomes AF: 0.000212 AC: 32 AN: 150756 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00132

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: 0.000133

Gnomad OTH AF: 0.000961

GnomAD3 exomes AF: 0.000126 AC: 31 AN: 245768 Hom.: 0 AF XY: 0.000142 AC XY: 19 AN XY: 133958

Gnomad AFR exome AF: 0.000133

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.000166

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000163 AC: 238 AN: 1456486 Hom.: 0 Cov.: 29 AF XY: 0.000164 AC XY: 119 AN XY: 724588

Gnomad4 AFR exome AF: 0.0000609

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000178

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000212 AC: 32 AN: 150862 Hom.: 0 Cov.: 21 AF XY: 0.000217 AC XY: 16 AN XY: 73690

Gnomad4 AFR AF: 0.0000247

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000133

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.000288 Hom.: 0

ExAC AF: 0.0000992 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.92A>G (p.H31R) alteration is located in exon 3 (coding exon 3) of the CFC1 gene. This alteration results from a A to G substitution at nucleotide position 92, causing the histidine (H) at amino acid position 31 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	8.0
DANN	Benign	0.33
DEOGEN2	Benign	0.18	.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.45	T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.044	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.9	.;.;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.8	.;.;D
REVEL	Benign	0.12
Sift	Benign	0.12	.;.;T
Sift4G	Benign	0.070	T;D;T
Polyphen		0.20	.;.;B
Vest4		0.24
MutPred		0.20		Gain of MoRF binding (P = 0.0119);Gain of MoRF binding (P = 0.0119);Gain of MoRF binding (P = 0.0119);
MVP		0.093
MPC		1.7
ClinPred		0.041	T
GERP RS		0.30
Varity_R		0.072
gMVP		0.068

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

LitVar

Other links and lift over

dbSNP: rs745944102; hg19: chr2-131356370;