Variant 5-73006534-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_138782.3(FCHO2):c.585G>A(p.Met195Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,562,176 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

FCHO2
NM_138782.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.10

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]

FCHO2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCHO2	NM_138782.3 linkuse as main transcript	c.585G>A	p.Met195Ile	missense_variant	6/26	ENST00000430046.7	NP_620137.2	Q0JRZ9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FCHO2	ENST00000430046.7 linkuse as main transcript	c.585G>A	p.Met195Ile	missense_variant	6/26	1	NM_138782.3	ENSP00000393776.2	Q0JRZ9-1
FCHO2	ENST00000287761.7 linkuse as main transcript	c.585G>A	p.Met195Ile	missense_variant	6/11	1		ENSP00000287761.6	H7BXJ4
FCHO2	ENST00000512348.5 linkuse as main transcript	c.585G>A	p.Met195Ile	missense_variant	6/25	2		ENSP00000427296.1	Q0JRZ9-3
FCHO2	ENST00000507345.6 linkuse as main transcript	c.510G>A	p.Met170Ile	missense_variant	5/7	5		ENSP00000426842.2	H0YAE2

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000531

AC:

AN:

188406

Hom.:

AF XY:

0.00

AC XY:

AN XY:

101602

show subpopulations

Gnomad AFR exome

AF:

0.0000858

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000567

AC:

AN:

1409924

Hom.:

Cov.:

AF XY:

0.00000573

AC XY:

AN XY:

698468

show subpopulations

Gnomad4 AFR exome

AF:

0.0000962

Gnomad4 AMR exome

AF:

0.0000844

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:

0.00

Gnomad4 OTH exome

AF:

0.0000343

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000136

ESP6500AA

AF:

0.000279

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000831

AC:

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 submitter

clinical testing

Ambry Genetics

Jan 10, 2022

The c.585G>A (p.M195I) alteration is located in exon 6 (coding exon 6) of the FCHO2 gene. This alteration results from a G to A substitution at nucleotide position 585, causing the methionine (M) at amino acid position 195 to be replaced by an isoleucine (I). 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

0.98

BayesDel_addAF

Uncertain

0.020

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T;.;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.56

D;D;D;D

MetaSVM

Benign

-0.59

MutationAssessor

Pathogenic

2.9

M;.;M;.

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.7

D;.;N;D

REVEL

Benign

0.28

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Uncertain

0.031

D;D;T;D

Polyphen

0.98

D;.;.;.

Vest4

0.69

MutPred

0.42

Loss of disorder (P = 0.0948);.;Loss of disorder (P = 0.0948);Loss of disorder (P = 0.0948);

MVP

0.60

MPC

0.36

ClinPred

0.97

GERP RS

4.9

Varity_R

0.87

gMVP

0.71

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over