Genetic Variant COX8C:p.Val46Ala (chr14-93348038-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_182971.3(COX8C):c.137T>C(p.Val46Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

COX8C
NM_182971.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.418

Publications

0 publications found

Variant links:

Genes affected

COX8C (HGNC:24382): (cytochrome c oxidase subunit 8C) Predicted to be involved in mitochondrial electron transport, cytochrome c to oxygen. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

COX8C links:

UNC79 (HGNC:19966): (unc-79 homolog, NALCN channel complex subunit) The NALCN channel is responsible for Na(+) leak currents. The protein encoded by this gene, along with UNC80, is an accessory subunit of the NALCN channel that contributes to the Ca(2+) sensitivity of the channel. [provided by RefSeq, Sep 2016]

UNC79 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

UNC79 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20808837).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182971.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COX8C	NM_182971.3	MANE Select	c.137T>C	p.Val46Ala	missense	Exon 2 of 2	NP_892016.1	Q7Z4L0
UNC79	NM_020818.5		c.-351+14515T>C		intron	N/A	NP_065869.3	Q9P2D8-2
UNC79	NR_144398.1		n.335T>C		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX8C	ENST00000342144.3	TSL:1 MANE Select	c.137T>C	p.Val46Ala	missense	Exon 2 of 2	ENSP00000340568.2	Q7Z4L0
	UNC79	ENST00000256339.8	TSL:5	c.-351+14515T>C		intron	N/A	ENSP00000256339.4	Q9P2D8-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1456556

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725008

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33374

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1107264

Other (OTH)

AF:

0.00

AC:

AN:

60218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.26

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.023

M_CAP

Benign

0.0043

MetaRNN

Benign

0.21

MetaSVM

Benign

-1.0

PhyloP100

0.42

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.040

Sift

Uncertain

0.011

Sift4G

Uncertain

0.020

Polyphen

0.57

Vest4

0.27

MutPred

0.65

Gain of sheet (P = 0.0221)

MVP

0.014

MPC

0.50

ClinPred

0.31

GERP RS

0.10

Varity_R

0.19

gMVP

0.57

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over