5-72990505-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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

Scores

2
4
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.952
Variant links:
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]

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ACMG classification

Classification made for transcript

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/exons MANE Protein UniProt
FCHO2NM_138782.3 linkc.228C>G p.Phe76Leu missense_variant 4/26 ENST00000430046.7 NP_620137.2 Q0JRZ9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FCHO2ENST00000430046.7 linkc.228C>G p.Phe76Leu missense_variant 4/261 NM_138782.3 ENSP00000393776.2 Q0JRZ9-1
FCHO2ENST00000287761.7 linkc.228C>G p.Phe76Leu missense_variant 4/111 ENSP00000287761.6 H7BXJ4
FCHO2ENST00000512348.5 linkc.228C>G p.Phe76Leu missense_variant 4/252 ENSP00000427296.1 Q0JRZ9-3
FCHO2ENST00000507345.6 linkc.153C>G p.Phe51Leu missense_variant 3/75 ENSP00000426842.2 H0YAE2

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
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 16, 2024The 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; API