17-44557787-C-G

Position:

• chr17-44557787-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001466.4(FZD2):​c.99C>G​(p.Ile33Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: FZD2 NM_001466.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.390

Genes affected

FZD2 (HGNC:4040): (frizzled class receptor 2) This intronless gene is a member of the frizzled gene family. Members of this family encode seven-transmembrane domain proteins that are receptors for the wingless type MMTV integration site family of signaling proteins. This gene encodes a protein that is coupled to the beta-catenin canonical signaling pathway. Competition between the wingless-type MMTV integration site family, member 3A and wingless-type MMTV integration site family, member 5A gene products for binding of this protein is thought to regulate the beta-catenin-dependent and -independent pathways. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FZD2. . Gene score misZ 3.6675 (greater than the threshold 3.09). Trascript score misZ 3.5466 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant Robinow syndrome, autosomal dominant omodysplasia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15820679).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FZD2	NM_001466.4	c.99C>G	p.Ile33Met	missense_variant	1/1	ENST00000315323.5	NP_001457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FZD2	ENST00000315323.5	c.99C>G	p.Ile33Met	missense_variant	1/1	6	NM_001466.4	ENSP00000323901.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461468 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727048

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 24, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with FZD2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 33 of the FZD2 protein (p.Ile33Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.17
Sift	Benign	0.030	D
Sift4G	Benign	0.15	T
Polyphen		0.76	P
Vest4		0.21
MutPred		0.38		Loss of catalytic residue at I33 (P = 0.004);
MVP		0.48
ClinPred		0.31	T
GERP RS		-1.5
Varity_R		0.083
gMVP		0.38

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: rs1017947835; hg19: chr17-42635155;