rs74917403

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr14-103563042-C-A
• chr14-103563042-C-G
• chr14-103563042-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001370595.2(COA8):​c.41C>A​(p.Pro14His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,391,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P14S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: COA8 NM_001370595.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U: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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017921954).

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>A	p.Pro14His	missense	Exon 1 of 5	NP_001357524.1	A0A6Q8JUI0
	COA8	NM_001302653.2		c.41C>A	p.Pro14His	missense	Exon 1 of 6	NP_001289582.2	G3V4L6
	COA8	NM_001302654.2		c.41C>A	p.Pro14His	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>A	p.Pro14His	missense	Exon 1 of 5	ENSP00000386485.3	A0A6Q8JUI0
	ENSG00000256500	ENST00000472726.3	TSL:2	c.41C>A	p.Pro14His	missense	Exon 1 of 18	ENSP00000439065.2	E7EVH7
	COA8	ENST00000674165.1		c.80C>A	p.Pro27His	missense	Exon 1 of 5	ENSP00000501341.1	Q96IL0-1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000346 AC: 5 AN: 144486 AF XY: 0.0000379

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000174

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 23 AN: 1391010 Hom.: 0 Cov.: 32 AF XY: 0.0000204 AC XY: 14 AN XY: 687400

African (AFR) AF: 0.0000314 AC: 1 AN: 31872

American (AMR) AF: 0.000109 AC: 4 AN: 36790

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

East Asian (EAS) AF: 0.0000273 AC: 1 AN: 36586

South Asian (SAS) AF: 0.0000499 AC: 4 AN: 80124

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5410

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1081968

Other (OTH) AF: 0.0000172 AC: 1 AN: 58030

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000373 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.29
DANN	Benign	0.72
DEOGEN2	Benign	0.0067	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0045	N
LIST_S2	Benign	0.29	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.81	L
PhyloP100		-2.0
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.048
Sift	Benign	0.27	T
Sift4G	Benign	0.11	T
Polyphen		0.41	B
Vest4		0.12
MutPred		0.35		Gain of catalytic residue at K22 (P = 0.009)
MVP		0.17
MPC		0.22
ClinPred		0.097	T
GERP RS		-7.4
PromoterAI		0.0017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.058
gMVP		0.29
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

Other links and lift over

dbSNP: rs74917403; hg19: chr14-104029379;