X-155027008-C-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_023934.4(FUNDC2):c.70C>G(p.Arg24Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 112,118 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000064 ( 0 hom. 3 hem. )

Failed GnomAD Quality Control

Consequence

FUNDC2
NM_023934.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.409

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:

F8 (HGNC:3546): (coagulation factor VIII) This gene encodes coagulation factor VIII, which participates in the intrinsic pathway of blood coagulation; factor VIII is a cofactor for factor IXa which, in the presence of Ca+2 and phospholipids, converts factor X to the activated form Xa. This gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity. Defects in this gene results in hemophilia A, a common recessive X-linked coagulation disorder. [provided by RefSeq, Jul 2008]

F8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04962167).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUNDC2	NM_023934.4 link	c.70C>G	p.Arg24Gly	missense_variant	Exon 1 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.70C>G	p.Arg24Gly	missense_variant	Exon 1 of 5	1	NM_023934.4	ENSP00000358510.3		Q9BWH2

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112118

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34284

show subpopulations

Gnomad AFR

AF:

0.0000324

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000124

AC:

AN:

161437

Hom.:

AF XY:

0.00

AC XY:

AN XY:

52677

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:

0.0000284

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000642

AC:

AN:

1090666

Hom.:

Cov.:

AF XY:

0.00000839

AC XY:

AN XY:

357702

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:

0.00000834

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112118

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34284

show subpopulations

Gnomad4 AFR

AF:

0.0000324

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:

0.0000189

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000829

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.70C>G (p.R24G) alteration is located in exon 1 (coding exon 1) of the FUNDC2 gene. This alteration results from a C to G substitution at nucleotide position 70, causing the arginine (R) at amino acid position 24 to be replaced by a glycine (G). 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

0.081

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.8

DANN

Benign

0.45

DEOGEN2

Benign

0.017

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.48

M_CAP

Benign

0.028

MetaRNN

Benign

0.050

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.67

REVEL

Benign

0.028

Sift

Benign

0.062

Sift4G

Benign

0.60

Polyphen

0.0010

Vest4

0.14

MutPred

0.21

Gain of relative solvent accessibility (P = 0.0166);

MVP

0.043

MPC

0.32

ClinPred

0.025

GERP RS

0.96

Varity_R

0.064

gMVP

0.27

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