NM_032545.4:c.588C>A

Variant names:

• chr2-130592961-G-T
• rs587780885
• NM_032545.4:c.588C>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_032545.4(CFC1):​c.588C>A​(p.Pro196Pro) variant causes a synonymous 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 0.034 (31 hom., cov: 8)
  • Exomes 𝑓: 0.0073 (27 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFC1 NM_032545.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -6.16
• Publications: 1 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023072362).
• BP6: Variant 2-130592961-G-T is Benign according to our data. Variant chr2-130592961-G-T is described in ClinVar as Benign. ClinVar VariationId is 136736.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-6.16 with no splicing effect.

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.588C>A	p.Pro196Pro	synonymous	Exon 6 of 6	NP_115934.1	P0CG37
	CFC1	NM_001270420.2		c.473C>A	p.Pro158Gln	missense	Exon 5 of 5	NP_001257349.1	A0A087WWV2
	CFC1	NM_001270421.2		c.363C>A	p.Pro121Pro	synonymous	Exon 4 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.588C>A	p.Pro196Pro	synonymous	Exon 6 of 6	ENSP00000259216.5	P0CG37
	CFC1	ENST00000615342.4	TSL:5	c.473C>A	p.Pro158Gln	missense	Exon 5 of 5	ENSP00000480526.1	A0A087WWV2
	CFC1	ENST00000621673.4	TSL:2	c.363C>A	p.Pro121Pro	synonymous	Exon 4 of 4	ENSP00000480843.1	A0A087WX98

Frequencies

GnomAD3 genomes AF: 0.0344 AC: 2182 AN: 63360 Hom.: 31 Cov.: 8

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.00431

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0210

Gnomad NFE AF: 0.000427

Gnomad OTH AF: 0.0456

GnomAD2 exomes AF: 0.0222 AC: 1106 AN: 49756 AF XY: 0.0188

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.00504

Gnomad EAS exome AF: 0.000135

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00852

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00729 AC: 3179 AN: 436368 Hom.: 27 Cov.: 0 AF XY: 0.00607 AC XY: 1387 AN XY: 228514

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

African (AFR) AF: 0.190 AC: 2166 AN: 11430

American (AMR) AF: 0.0150 AC: 272 AN: 18162

Ashkenazi Jewish (ASJ) AF: 0.00465 AC: 63 AN: 13534

East Asian (EAS) AF: 0.0000328 AC: 1 AN: 30504

South Asian (SAS) AF: 0.000366 AC: 16 AN: 43686

European-Finnish (FIN) AF: 0.000242 AC: 7 AN: 28900

Middle Eastern (MID) AF: 0.0114 AC: 22 AN: 1926

European-Non Finnish (NFE) AF: 0.000826 AC: 217 AN: 262836

Other (OTH) AF: 0.0163 AC: 415 AN: 25390

⚠️ 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: 0.0344 AC: 2178 AN: 63326 Hom.: 31 Cov.: 8 AF XY: 0.0365 AC XY: 968 AN XY: 26526

African (AFR) AF: 0.151 AC: 1974 AN: 13064

American (AMR) AF: 0.0277 AC: 138 AN: 4980

Ashkenazi Jewish (ASJ) AF: 0.00431 AC: 9 AN: 2088

East Asian (EAS) AF: 0.00 AC: 0 AN: 3016

South Asian (SAS) AF: 0.00 AC: 0 AN: 1702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1836

Middle Eastern (MID) AF: 0.0190 AC: 4 AN: 210

European-Non Finnish (NFE) AF: 0.000427 AC: 15 AN: 35150

Other (OTH) AF: 0.0452 AC: 38 AN: 840

Alfa AF: 0.00700 Hom.: 3

ExAC AF: 0.000387 AC: 1

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-1.0	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	5.0
DANN	Benign	0.67
FATHMM_MKL	Benign	0.00029	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0023	T
PhyloP100		-6.2
Vest4		0.14
GERP RS		-3.1
Mutation Taster		=100/0	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: rs587780885; hg19: chr2-131350534;