14-103563041-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 14/20 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:5
• 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=0.0045024753).
• BP6: Variant 14-103563041-C-G is Benign according to our data. Variant chr14-103563041-C-G is described in ClinVar as Benign. ClinVar VariationId 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.

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>G	p.Pro14Ala	missense	Exon 1 of 5	NP_001357524.1	A0A6Q8JUI0
	COA8	NM_001302653.2		c.40C>G	p.Pro14Ala	missense	Exon 1 of 6	NP_001289582.2	G3V4L6
	COA8	NM_001302654.2		c.40C>G	p.Pro14Ala	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>G	p.Pro14Ala	missense	Exon 1 of 5	ENSP00000386485.3	A0A6Q8JUI0
	ENSG00000256500	ENST00000472726.3	TSL:2	c.40C>G	p.Pro14Ala	missense	Exon 1 of 18	ENSP00000439065.2	E7EVH7
	COA8	ENST00000674165.1		c.79C>G	p.Pro27Ala	missense	Exon 1 of 5	ENSP00000501341.1	Q96IL0-1

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

GnomAD2 exomes AF: 0.258 AC: 37220 AN: 144426 AF XY: 0.264

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 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

African (AFR) AF: 0.289 AC: 9205 AN: 31810

American (AMR) AF: 0.177 AC: 6485 AN: 36676

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 8597 AN: 25048

East Asian (EAS) AF: 0.105 AC: 3842 AN: 36716

South Asian (SAS) AF: 0.240 AC: 19188 AN: 79954

European-Finnish (FIN) AF: 0.288 AC: 10065 AN: 34936

Middle Eastern (MID) AF: 0.358 AC: 1902 AN: 5314

European-Non Finnish (NFE) AF: 0.351 AC: 379141 AN: 1081180

Other (OTH) AF: 0.314 AC: 18224 AN: 57956

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

African (AFR) AF: 0.287 AC: 11920 AN: 41544

American (AMR) AF: 0.250 AC: 3820 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 1229 AN: 3468

East Asian (EAS) AF: 0.0793 AC: 411 AN: 5180

South Asian (SAS) AF: 0.224 AC: 1082 AN: 4826

European-Finnish (FIN) AF: 0.277 AC: 2930 AN: 10596

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.351 AC: 23839 AN: 67962

Other (OTH) AF: 0.310 AC: 655 AN: 2112

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Mitochondrial complex IV deficiency, nuclear type 17 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.26	N
PhyloP100		-1.4
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.028
Sift	Benign	0.78	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.073
MPC		0.061
ClinPred		0.00089	T
GERP RS		-1.8
PromoterAI		0.042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.023
gMVP		0.20
Mutation Taster		=98/2	polymorphism (auto)

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; COSMIC: COSV54572351; COSMIC: COSV54572351;