chr2-130597533-C-T

Variant names:

• chr2-130597533-C-T
• rs199715380
• NM_032545.4:c.433G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_032545.4(CFC1):​c.433G>A​(p.Ala145Thr) 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: not found (cov: 0)
  • Exomes 𝑓: 0.072 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFC1 NM_032545.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.143
• Publications: 7 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17100677).
• BP6: Variant 2-130597533-C-T is Benign according to our data. Variant chr2-130597533-C-T is described in ClinVar as Benign. ClinVar VariationId is 136735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.433G>A	p.Ala145Thr	missense	Exon 5 of 6	NP_115934.1	P0CG37
	CFC1	NM_001270420.2		c.318G>A	p.Gly106Gly	synonymous	Exon 4 of 5	NP_001257349.1	A0A087WWV2
	CFC1	NM_001270421.2		c.247+1109G>A		intron	N/A	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.433G>A	p.Ala145Thr	missense	Exon 5 of 6	ENSP00000259216.5	P0CG37
	CFC1	ENST00000615342.4	TSL:5	c.318G>A	p.Gly106Gly	synonymous	Exon 4 of 5	ENSP00000480526.1	A0A087WWV2
	CFC1	ENST00000621673.4	TSL:2	c.247+1109G>A		intron	N/A	ENSP00000480843.1	A0A087WX98

Frequencies

GnomAD3 genomes AC: 0 AN: 0 Hom.: 0 Cov.: 0

GnomAD2 exomes AF: 0.0465 AC: 172 AN: 3700 AF XY: 0.0452

Gnomad AFR exome AF: 0.0422

Gnomad AMR exome AF: 0.0496

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.00103

Gnomad FIN exome AF: 0.0294

Gnomad NFE exome AF: 0.0875

Gnomad OTH exome AF: 0.0700

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0717 AC: 5279 AN: 73600 Hom.: 5 Cov.: 0 AF XY: 0.0688 AC XY: 2649 AN XY: 38478

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

African (AFR) AF: 0.0207 AC: 27 AN: 1304

American (AMR) AF: 0.0606 AC: 236 AN: 3896

Ashkenazi Jewish (ASJ) AF: 0.0973 AC: 176 AN: 1808

East Asian (EAS) AF: 0.00101 AC: 4 AN: 3972

South Asian (SAS) AF: 0.0357 AC: 378 AN: 10574

European-Finnish (FIN) AF: 0.0504 AC: 126 AN: 2502

Middle Eastern (MID) AF: 0.0847 AC: 20 AN: 236

European-Non Finnish (NFE) AF: 0.0887 AC: 4034 AN: 45468

Other (OTH) AF: 0.0724 AC: 278 AN: 3840

⚠️ 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: AC0;AS_VQSR AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

Alfa AF: 0.0282 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Heterotaxy, visceral, 2, autosomal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.79
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0052	N
LIST_S2	Benign	0.20	T
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.95	T
PhyloP100		0.14
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.22
Sift	Benign	0.73	T
Sift4G	Benign	0.62	T
Polyphen		0.0010	B
Vest4		0.13
MPC		1.3
ClinPred		0.00030	T
GERP RS		-0.52
Varity_R		0.031
gMVP		0.17
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs199715380; hg19: chr2-131355106;