14-93348038-T-C

Variant names:

• chr14-93348038-T-C
• NM_182971.3:c.137T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COX8C NM_182971.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.418

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]

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]

ACMG classification

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=0.20808837).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX8C	NM_182971.3	c.137T>C	p.Val46Ala	missense_variant	Exon 2 of 2	ENST00000342144.3	NP_892016.1
UNC79	NM_020818.5	c.-351+14515T>C		intron_variant	Intron 1 of 49		NP_065869.3
UNC79	XM_011537027.3	c.-180+14515T>C		intron_variant	Intron 1 of 51		XP_011535329.1
UNC79	NR_144398.1	n.335T>C		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX8C	ENST00000342144.3	c.137T>C	p.Val46Ala	missense_variant	Exon 2 of 2	1	NM_182971.3	ENSP00000340568.2
UNC79	ENST00000256339.8	c.-351+14515T>C		intron_variant	Intron 1 of 49	5		ENSP00000256339.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456556 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2 AN XY: 725008

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.137T>C (p.V46A) alteration is located in exon 2 (coding exon 2) of the COX8C gene. This alteration results from a T to C substitution at nucleotide position 137, causing the valine (V) at amino acid position 46 to be replaced by an alanine (A). 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	0.19
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Benign	0.73
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.023	N
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.040
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.020	D
Polyphen		0.57	P
Vest4		0.27
MutPred		0.65		Gain of sheet (P = 0.0221);
MVP		0.014
MPC		0.50
ClinPred		0.31	T
GERP RS		0.10
Varity_R		0.19
gMVP		0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-93814384;