14-103563041-C-A

Variant names:

• chr14-103563041-C-A
• rs2274268
• NM_001370595.2:c.40C>A

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.40C>A​(p.Pro14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 1,543,774 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely 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 0.0018 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0031 (10 hom.)
• Consequence: COA8 NM_001370595.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.36
• Publications: 37 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=0.0047018826).
• BP6: Variant 14-103563041-C-A is Benign according to our data. Variant chr14-103563041-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 381449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00178 (271/152220) while in subpopulation NFE AF = 0.00328 (223/67980). AF 95% confidence interval is 0.00293. There are 0 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.40C>A	p.Pro14Thr	missense	Exon 1 of 5	NP_001357524.1	A0A6Q8JUI0
	COA8	NM_001302653.2		c.40C>A	p.Pro14Thr	missense	Exon 1 of 6	NP_001289582.2	G3V4L6
	COA8	NM_001302654.2		c.40C>A	p.Pro14Thr	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.40C>A	p.Pro14Thr	missense	Exon 1 of 5	ENSP00000386485.3	A0A6Q8JUI0
	ENSG00000256500	ENST00000472726.3	TSL:2	c.40C>A	p.Pro14Thr	missense	Exon 1 of 18	ENSP00000439065.2	E7EVH7
	COA8	ENST00000674165.1		c.79C>A	p.Pro27Thr	missense	Exon 1 of 5	ENSP00000501341.1	Q96IL0-1

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 271 AN: 152102 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00193 AC: 279 AN: 144426 AF XY: 0.00198

Gnomad AFR exome AF: 0.00120

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000839

Gnomad FIN exome AF: 0.000474

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00190

GnomAD4 exome AF: 0.00307 AC: 4270 AN: 1391554 Hom.: 10 Cov.: 38 AF XY: 0.00296 AC XY: 2039 AN XY: 687708

African (AFR) AF: 0.000752 AC: 24 AN: 31894

American (AMR) AF: 0.00187 AC: 69 AN: 36910

Ashkenazi Jewish (ASJ) AF: 0.000119 AC: 3 AN: 25166

East Asian (EAS) AF: 0.0000544 AC: 2 AN: 36738

South Asian (SAS) AF: 0.000511 AC: 41 AN: 80196

European-Finnish (FIN) AF: 0.000686 AC: 24 AN: 34998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5344

European-Non Finnish (NFE) AF: 0.00369 AC: 3991 AN: 1082250

Other (OTH) AF: 0.00200 AC: 116 AN: 58058

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152220 Hom.: 0 Cov.: 34 AF XY: 0.00161 AC XY: 120 AN XY: 74424

African (AFR) AF: 0.000602 AC: 25 AN: 41548

American (AMR) AF: 0.000784 AC: 12 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00328 AC: 223 AN: 67980

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00119 Hom.: 895

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00415 AC: 16

ExAC AF: 0.00124 AC: 129

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	COA8-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.25
DANN	Benign	0.78
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0074	N
LIST_S2	Benign	0.17	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.4
PROVEAN	Benign	2.0	N
REVEL	Benign	0.051
Sift	Uncertain	0.029	D
MVP		0.014
ClinPred		0.000059	T
GERP RS		-1.8
PromoterAI		0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.030
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs2274268; hg19: chr14-104029378;