14-103563042-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 13/19 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. P14A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0052 ( 4 hom., cov: 34)

Exomes 𝑓: 0.00057 ( 5 hom. )

Consequence

COA8
NM_001370595.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.03

Variant links:

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]

COA8 links:

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]

KLC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COA8	NM_001370595.2 linkuse as main transcript	c.41C>G	p.Pro14Arg	missense_variant	1/5	ENST00000409074.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COA8	ENST00000409074.8 linkuse as main transcript	c.41C>G	p.Pro14Arg	missense_variant	1/5	1	NM_001370595.2	P1

Frequencies

GnomAD3 genomes

AF:

0.00515

AC:

784

AN:

152210

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00124

AC:

179

AN:

144486

Hom.:

AF XY:

0.000986

AC XY:

AN XY:

79108

show subpopulations

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 SAS exome

AF:

0.000934

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.:

Cov.:

AF XY:

0.000512

AC XY:

352

AN XY:

687400

show subpopulations

Gnomad4 AFR exome

AF:

0.0191

Gnomad4 AMR exome

AF:

0.000571

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000911

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000213

Gnomad4 OTH exome

AF:

0.000999

GnomAD4 genome

AF:

0.00517

AC:

788

AN:

152328

Hom.:

Cov.:

AF XY:

0.00478

AC XY:

356

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0180

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.000324

Hom.:

Bravo

AF:

0.00578

ESP6500AA

AF:

0.00860

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00104

AC:

112

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 02, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.50

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

LIST_S2

Benign

0.26

T;T;T

MetaRNN

Benign

0.0032

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

L;.;.

MutationTaster

Benign

1.0

PROVEAN

Benign

-0.74

N;N;N

REVEL

Benign

0.028

Sift

Benign

0.33

T;T;T

Sift4G

Benign

0.56

T;D;T

Polyphen

0.0

B;.;.

Vest4

0.099

MVP

0.16

MPC

0.067

ClinPred

0.012

GERP RS

-7.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.042

gMVP

0.29

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over