14-103563042-C-G

Variant names:

• chr14-103563042-C-G
• rs74917403
• NM_001370595.2:c.41C>G

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.41C>G​(p.Pro14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,543,338 control chromosomes in the GnomAD database, including 9 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 0.0052 (4 hom., cov: 34)
  • Exomes 𝑓: 0.00057 (5 hom.)
• Consequence: COA8 NM_001370595.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.03
• Publications: 1 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=0.0032265782).
• BP6: Variant 14-103563042-C-G is Benign according to our data. Variant chr14-103563042-C-G is described in ClinVar as Benign. ClinVar VariationId is 382991.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 = 0.00517 (788/152328) while in subpopulation AFR AF = 0.018 (749/41580). AF 95% confidence interval is 0.0169. There are 4 homozygotes in GnomAd4. There are 356 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.41C>G	p.Pro14Arg	missense	Exon 1 of 5	NP_001357524.1	A0A6Q8JUI0
	COA8	NM_001302653.2		c.41C>G	p.Pro14Arg	missense	Exon 1 of 6	NP_001289582.2	G3V4L6
	COA8	NM_001302654.2		c.41C>G	p.Pro14Arg	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.41C>G	p.Pro14Arg	missense	Exon 1 of 5	ENSP00000386485.3	A0A6Q8JUI0
	ENSG00000256500	ENST00000472726.3	TSL:2	c.41C>G	p.Pro14Arg	missense	Exon 1 of 18	ENSP00000439065.2	E7EVH7
	COA8	ENST00000674165.1		c.80C>G	p.Pro27Arg	missense	Exon 1 of 5	ENSP00000501341.1	Q96IL0-1

Frequencies

GnomAD3 genomes AF: 0.00515 AC: 784 AN: 152210 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00124 AC: 179 AN: 144486 AF XY: 0.000986

Gnomad AFR exome AF: 0.0195

Gnomad AMR exome AF: 0.000314

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000853

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000348

Gnomad OTH exome AF: 0.000471

GnomAD4 exome AF: 0.000568 AC: 790 AN: 1391010 Hom.: 5 Cov.: 32 AF XY: 0.000512 AC XY: 352 AN XY: 687400

African (AFR) AF: 0.0191 AC: 608 AN: 31872

American (AMR) AF: 0.000571 AC: 21 AN: 36788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25188

East Asian (EAS) AF: 0.00 AC: 0 AN: 36586

South Asian (SAS) AF: 0.000911 AC: 73 AN: 80124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35042

Middle Eastern (MID) AF: 0.00129 AC: 7 AN: 5410

European-Non Finnish (NFE) AF: 0.0000213 AC: 23 AN: 1081970

Other (OTH) AF: 0.000999 AC: 58 AN: 58030

GnomAD4 genome AF: 0.00517 AC: 788 AN: 152328 Hom.: 4 Cov.: 34 AF XY: 0.00478 AC XY: 356 AN XY: 74502

African (AFR) AF: 0.0180 AC: 749 AN: 41580

American (AMR) AF: 0.00118 AC: 18 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68008

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.000324 Hom.: 0

Bravo AF: 0.00578

ESP6500AA AF: 0.00860 AC: 36

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00104 AC: 112

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.22
DANN	Benign	0.58
DEOGEN2	Benign	0.0057	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		-2.0
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.028
Sift	Benign	0.33	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.099
MVP		0.16
MPC		0.067
ClinPred		0.012	T
GERP RS		-7.4
PromoterAI		0.048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.042
gMVP		0.29
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: rs74917403; hg19: chr14-104029379;