Genetic Variant C8orf58:p.Pro234Leu (chr8-22602015-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_001013842.3(C8orf58):c.701C>T(p.Pro234Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000698 in 1,576,232 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

C8orf58
NM_001013842.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.618

Variant links:

Genes affected

C8orf58 (HGNC:32233): (chromosome 8 open reading frame 58)

C8orf58 links:

ENSG00000248235 (HGNC:):

ENSG00000248235 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=0.029872507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C8orf58	NM_001013842.3 link	c.701C>T	p.Pro234Leu	missense_variant	Exon 4 of 7	ENST00000289989.10	NP_001013864.1	Q8NAV2-1
C8orf58	NM_173686.3 link	c.701C>T	p.Pro234Leu	missense_variant	Exon 4 of 7		NP_775957.2	Q8NAV2-2
C8orf58	NM_001198827.2 link	c.701C>T	p.Pro234Leu	missense_variant	Exon 4 of 6		NP_001185756.1	A0A087WX44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C8orf58	ENST00000289989.10 link	c.701C>T	p.Pro234Leu	missense_variant	Exon 4 of 7	5	NM_001013842.3	ENSP00000289989.5		Q8NAV2-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

218924

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

118382

show subpopulations

Gnomad AFR exome

AF:

0.000139

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00206

Gnomad EAS exome

AF:

0.000115

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000409

Gnomad OTH exome

AF:

0.000376

GnomAD4 exome

AF:

0.0000660

AC:

AN:

1423966

Hom.:

Cov.:

AF XY:

0.0000626

AC XY:

AN XY:

703086

show subpopulations

Gnomad4 AFR exome

AF:

0.000215

Gnomad4 AMR exome

AF:

0.0000476

Gnomad4 ASJ exome

AF:

0.00216

Gnomad4 EAS exome

AF:

0.000129

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000197

Gnomad4 NFE exome

AF:

0.0000138

Gnomad4 OTH exome

AF:

0.000205

GnomAD4 genome

AF:

0.000105

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000181

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000662

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.701C>T (p.P234L) alteration is located in exon 4 (coding exon 4) of the C8orf58 gene. This alteration results from a C to T substitution at nucleotide position 701, causing the proline (P) at amino acid position 234 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

0.074

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.065

.;.;.;T;.;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.68

T;T;T;T;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.030

T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.2

.;L;.;L;.;.

PROVEAN

Uncertain

-3.0

.;D;.;D;.;D

REVEL

Benign

0.13

Sift

Benign

0.47

.;T;.;T;.;D

Sift4G

Uncertain

0.013

D;D;D;D;D;D

Polyphen

0.45

.;B;.;B;.;.

Vest4

0.12, 0.086, 0.090, 0.11

MVP

0.35

MPC

0.048

ClinPred

0.032

GERP RS

3.2

Varity_R

0.047

gMVP

0.13

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