Genetic Variant C8orf82:p.Glu175Lys (chr8-144527470-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001001795.2(C8orf82):c.523G>A(p.Glu175Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,248,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

C8orf82
NM_001001795.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.30

Variant links:

Genes affected

C8orf82 (HGNC:33826): (chromosome 8 open reading frame 82)

C8orf82 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25551084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C8orf82	NM_001001795.2 link	c.523G>A	p.Glu175Lys	missense_variant	Exon 3 of 3	ENST00000524821.6	NP_001001795.1	Q6P1X6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
C8orf82	ENST00000524821.6 link	c.523G>A	p.Glu175Lys	missense_variant	Exon 3 of 3	1	NM_001001795.2	ENSP00000436621.1	Q6P1X6-1
C8orf82	ENST00000313465 link	c.*498G>A		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000316262.5	J3KNI2
C8orf82	ENST00000532827.1 link	c.655G>A	p.Glu219Lys	missense_variant	Exon 3 of 3	2		ENSP00000437092.1	H0YF29
C8orf82	ENST00000534680.5 link	n.523G>A		non_coding_transcript_exon_variant	Exon 3 of 4	5		ENSP00000434593.1	Q6P1X6-1

Frequencies

GnomAD3 genomes

AF:

0.000346

AC:

AN:

150264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00124

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000663

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

GnomAD4 exome

AF:

0.0000273

AC:

AN:

1098060

Hom.:

Cov.:

AF XY:

0.0000247

AC XY:

AN XY:

526814

show subpopulations

Gnomad4 AFR exome

AF:

0.00132

Gnomad4 AMR exome

AF:

0.000141

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:

0.00

GnomAD4 genome

AF:

0.000346

AC:

AN:

150372

Hom.:

Cov.:

AF XY:

0.000422

AC XY:

AN XY:

73444

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.0000662

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:

0.0000712

Hom.:

Bravo

AF:

0.000363

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.523G>A (p.E175K) alteration is located in exon 3 (coding exon 3) of the C8orf82 gene. This alteration results from a G to A substitution at nucleotide position 523, causing the glutamic acid (E) at amino acid position 175 to be replaced by a lysine (K). 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

Uncertain

0.45

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Benign

0.17

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.76

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.2

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.26

Sift

Benign

0.12

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.36

MutPred

0.45

Gain of ubiquitination at E175 (P = 0.017);

MVP

0.048

MPC

2.1

ClinPred

0.99

GERP RS

3.6

Varity_R

0.48

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