Genetic Variant FUNDC2:p.Ser53Leu (chrX-155033427-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_023934.4(FUNDC2):c.158C>T(p.Ser53Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000662 in 1,208,356 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000064 ( 0 hom. 1 hem. )

Consequence

FUNDC2
NM_023934.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.96

Variant links:

Genes affected

FUNDC2 (HGNC:24925): (FUN14 domain containing 2) Predicted to be involved in autophagy of mitochondrion. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

FUNDC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity FUND2_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.087308496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUNDC2	NM_023934.4 link	c.158C>T	p.Ser53Leu	missense_variant	Exon 2 of 5	ENST00000369498.8	NP_076423.2	Q9BWH2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUNDC2	ENST00000369498.8 link	c.158C>T	p.Ser53Leu	missense_variant	Exon 2 of 5	1	NM_023934.4	ENSP00000358510.3		Q9BWH2

Frequencies

GnomAD3 genomes

AF:

0.00000889

AC:

AN:

112549

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34701

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000187

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183317

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67769

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000639

AC:

AN:

1095807

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

361269

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000833

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000889

AC:

AN:

112549

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34701

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000187

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.158C>T (p.S53L) alteration is located in exon 2 (coding exon 2) of the FUNDC2 gene. This alteration results from a C to T substitution at nucleotide position 158, causing the serine (S) at amino acid position 53 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

Benign

0.14

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.019

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.79

M_CAP

Benign

0.043

MetaRNN

Benign

0.087

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.63

REVEL

Benign

0.050

Sift

Benign

0.36

Sift4G

Benign

0.16

Polyphen

0.028

Vest4

0.27

MutPred

0.30

Loss of disorder (P = 0.0202);

MVP

0.22

MPC

0.25

ClinPred

0.15

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.77

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