rs190920873

Variant names:

• chr14-103563024-A-G
• rs190920873
• NM_001370595.2:c.23A>G
• COA8 p.Lys8Arg

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001370595.2(COA8):​c.23A>G​(p.Lys8Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,556,566 control chromosomes in the GnomAD database, including 93 homozygotes. 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. K8K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (52 hom., cov: 34)
  • Exomes 𝑓: 0.0013 (41 hom.)
• Consequence: COA8 NM_001370595.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.224
• Publications: 0 publications found

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]

ENSG00000256500 (HGNC:):

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018971264).
• BP6: Variant 14-103563024-A-G is Benign according to our data. Variant chr14-103563024-A-G is described in ClinVar as Benign. ClinVar VariationId is 377320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0144 (2195/152276) while in subpopulation AFR AF = 0.05 (2078/41572). AF 95% confidence interval is 0.0482. There are 52 homozygotes in GnomAd4. There are 1035 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 52 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370595.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COA8	NM_001370595.2	MANE Select	c.23A>G	p.Lys8Arg	missense	Exon 1 of 5	NP_001357524.1	A0A6Q8JUI0
	COA8	NM_001302653.2		c.23A>G	p.Lys8Arg	missense	Exon 1 of 6	NP_001289582.2	G3V4L6
	COA8	NM_001302654.2		c.23A>G	p.Lys8Arg	missense	Exon 1 of 4	NP_001289583.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COA8	ENST00000409074.8	TSL:1 MANE Select	c.23A>G	p.Lys8Arg	missense	Exon 1 of 5	ENSP00000386485.3	A0A6Q8JUI0
	ENSG00000256500	ENST00000472726.3	TSL:2	c.23A>G	p.Lys8Arg	missense	Exon 1 of 18	ENSP00000439065.2	E7EVH7
	COA8	ENST00000674165.1		c.62A>G	p.Lys21Arg	missense	Exon 1 of 5	ENSP00000501341.1	Q96IL0-1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2191 AN: 152158 Hom.: 52 Cov.: 34

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00536

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.00360 AC: 585 AN: 162542 AF XY: 0.00293

Gnomad AFR exome AF: 0.0526

Gnomad AMR exome AF: 0.00351

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000118

Gnomad OTH exome AF: 0.00176

GnomAD4 exome AF: 0.00134 AC: 1881 AN: 1404290 Hom.: 41 Cov.: 32 AF XY: 0.00124 AC XY: 865 AN XY: 695098

African (AFR) AF: 0.0441 AC: 1434 AN: 32502

American (AMR) AF: 0.00394 AC: 154 AN: 39056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25254

East Asian (EAS) AF: 0.00 AC: 0 AN: 37918

South Asian (SAS) AF: 0.000111 AC: 9 AN: 81382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35272

Middle Eastern (MID) AF: 0.00319 AC: 17 AN: 5330

European-Non Finnish (NFE) AF: 0.0000312 AC: 34 AN: 1089082

Other (OTH) AF: 0.00398 AC: 233 AN: 58494

GnomAD4 genome AF: 0.0144 AC: 2195 AN: 152276 Hom.: 52 Cov.: 34 AF XY: 0.0139 AC XY: 1035 AN XY: 74464

African (AFR) AF: 0.0500 AC: 2078 AN: 41572

American (AMR) AF: 0.00536 AC: 82 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68002

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00786 Hom.: 9

Bravo AF: 0.0166

Asia WGS AF: 0.00289 AC: 10 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	COA8-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.086
DANN	Benign	0.51
DEOGEN2	Benign	0.00086	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00040	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.22
PROVEAN	Benign	0.060	N
REVEL	Benign	0.029
Sift	Benign	0.49	T
Sift4G	Benign	0.71	T
PromoterAI		0.043	Neutral
Varity_R		0.034
gMVP		0.15
Mutation Taster		=99/1	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs190920873;

hg19: chr14-104029361;

COSMIC: COSV107211545;

COSMIC: COSV107211545;