5-72990505-C-G

Variant names:

• chr5-72990505-C-G
• NM_138782.3:c.228C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_138782.3(FCHO2):​c.228C>G​(p.Phe76Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FCHO2 NM_138782.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.952

Genes affected

FCHO2 (HGNC:25180): (FCH and mu domain containing endocytic adaptor 2) Enables identical protein binding activity. Involved in clathrin coat assembly and clathrin-dependent endocytosis. Located in clathrin-coated pit and clathrin-coated vesicle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3094791).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCHO2	NM_138782.3	c.228C>G	p.Phe76Leu	missense_variant	Exon 4 of 26	ENST00000430046.7	NP_620137.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCHO2	ENST00000430046.7	c.228C>G	p.Phe76Leu	missense_variant	Exon 4 of 26	1	NM_138782.3	ENSP00000393776.2
FCHO2	ENST00000287761.7	c.228C>G	p.Phe76Leu	missense_variant	Exon 4 of 11	1		ENSP00000287761.6
FCHO2	ENST00000512348.5	c.228C>G	p.Phe76Leu	missense_variant	Exon 4 of 25	2		ENSP00000427296.1
FCHO2	ENST00000507345.6	c.153C>G	p.Phe51Leu	missense_variant	Exon 3 of 7	5		ENSP00000426842.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.228C>G (p.F76L) alteration is located in exon 4 (coding exon 4) of the FCHO2 gene. This alteration results from a C to G substitution at nucleotide position 228, causing the phenylalanine (F) at amino acid position 76 to be replaced by a leucine (L). 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	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.0068	T;T;.;T
Eigen	Benign	-0.066
Eigen_PC	Benign	-0.0058
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;L;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.6	D;.;N;D
REVEL	Benign	0.21
Sift	Benign	0.88	T;.;T;T
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.21	B;.;.;.
Vest4		0.74
MutPred		0.57		Gain of ubiquitination at K77 (P = 0.1504);.;Gain of ubiquitination at K77 (P = 0.1504);Gain of ubiquitination at K77 (P = 0.1504);
MVP		0.76
MPC		0.31
ClinPred		0.75	D
GERP RS		1.7
Varity_R		0.63
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-72286332;