14-103563041-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001370595.2(COA8):c.40C>G(p.Pro14Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 1,541,778 control chromosomes in the GnomAD database, including 85,328 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P14H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.30 (7317 hom., cov: 34)
  • Exomes 𝑓: 0.33 (78011 hom.)
• Consequence: COA8 NM_001370595.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.36

Genes affected

COA8 (HGNC:20492): (cytochrome c oxidase assembly factor 8) This gene encodes a protein that localizes to the mitochondria, where it stimulates the release of cytochrome c, thereby promoting programmed cell death. Mutations in this gene have been found in individuals with mitochondrial complex IV deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

KLC1 (HGNC:6387): (kinesin light chain 1) Conventional kinesin is a tetrameric molecule composed of two heavy chains and two light chains, and transports various cargos along microtubules toward their plus ends. The heavy chains provide the motor activity, while the light chains bind to various cargos. This gene encodes a member of the kinesin light chain family. It associates with kinesin heavy chain through an N-terminal domain, and six tetratricopeptide repeat (TPR) motifs are thought to be involved in binding of cargos such as vesicles, mitochondria, and the Golgi complex. Thus, kinesin light chains function as adapter molecules and not motors per se. Although previously named "kinesin 2", this gene is not a member of the kinesin-2 / kinesin heavy chain subfamily of kinesin motor proteins. Extensive alternative splicing produces isoforms with different C-termini that are proposed to bind to different cargos; however, the full-length nature and/or biological validity of most of these variants have not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045024753).
• BP6: Variant 14-103563041-C-G is Benign according to our data. Variant chr14-103563041-C-G is described in ClinVar as [Benign]. Clinvar id is 379942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COA8	NM_001370595.2	c.40C>G	p.Pro14Ala	missense_variant	1/5	ENST00000409074.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COA8	ENST00000409074.8	c.40C>G	p.Pro14Ala	missense_variant	1/5	1	NM_001370595.2	P1

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46261 AN: 152070 Hom.: 7315 Cov.: 34

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.354

Gnomad EAS AF: 0.0794

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.314

GnomAD3 exomes AF: 0.258 AC: 37220 AN: 144426 Hom.: 5619 AF XY: 0.264 AC XY: 20884 AN XY: 79108

Gnomad AFR exome AF: 0.269

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.337

Gnomad EAS exome AF: 0.0625

Gnomad SAS exome AF: 0.228

Gnomad FIN exome AF: 0.264

Gnomad NFE exome AF: 0.336

Gnomad OTH exome AF: 0.287

GnomAD4 exome AF: 0.329 AC: 456649 AN: 1389590 Hom.: 78011 Cov.: 38 AF XY: 0.327 AC XY: 224491 AN XY: 686606

Gnomad4 AFR exome AF: 0.289

Gnomad4 AMR exome AF: 0.177

Gnomad4 ASJ exome AF: 0.343

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.240

Gnomad4 FIN exome AF: 0.288

Gnomad4 NFE exome AF: 0.351

Gnomad4 OTH exome AF: 0.314

GnomAD4 genome AF: 0.304 AC: 46278 AN: 152188 Hom.: 7317 Cov.: 34 AF XY: 0.297 AC XY: 22089 AN XY: 74404

Gnomad4 AFR AF: 0.287

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.354

Gnomad4 EAS AF: 0.0793

Gnomad4 SAS AF: 0.224

Gnomad4 FIN AF: 0.277

Gnomad4 NFE AF: 0.351

Gnomad4 OTH AF: 0.310

Alfa AF: 0.248 Hom.: 895

Bravo AF: 0.301

TwinsUK AF: 0.356 AC: 1319

ALSPAC AF: 0.360 AC: 1388

ESP6500AA AF: 0.220 AC: 924

ESP6500EA AF: 0.294 AC: 2427

ExAC AF: 0.181 AC: 18859

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 04, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mitochondrial complex 4 deficiency, nuclear type 17 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	0.030
Dann	Benign	0.67
DEOGEN2	Benign	0.0042	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.29	T;T;T
MetaRNN	Benign	0.0045	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.26	N;.;.
MutationTaster	Benign	1.0	P
PROVEAN	Benign	-0.37	N;N;N
REVEL	Benign	0.028
Sift	Benign	0.78	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.073
MPC		0.061
ClinPred		0.00089	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.023
gMVP		0.20

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

Other links and lift over

dbSNP: rs2274268; hg19: chr14-104029378; COSMIC: COSV54572351; COSMIC: COSV54572351;