dbSNP rs146440690: COA6:p.Glu117Lys (chr1-234374366-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001206641.3(COA6):c.349G>A(p.Glu117Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,840 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

COA6
NM_001206641.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.87

Publications

7 publications found

Variant links:

Genes affected

COA6 (HGNC:18025): (cytochrome c oxidase assembly factor 6) This gene encodes a member of the cytochrome c oxidase subunit 6B family. The encoded protein associates with cytochrome c oxidase may act has an cytochrome c oxidase mitochondrial respiratory complex VI assembly factor. Mutations in this gene may be associated with fatal infantile cardiomyopathy. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2014]

COA6 Gene-Disease associations (from GenCC):

cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4
Inheritance: AR, Unknown Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

COA6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COA6	NM_001206641.3 link	c.349G>A	p.Glu117Lys	missense_variant	Exon 2 of 3	ENST00000366615.10	NP_001193570.2
COA6	NM_001012985.2 link	c.259G>A	p.Glu87Lys	missense_variant	Exon 2 of 3		NP_001013003.1
COA6	NM_001301733.1 link	c.121G>A	p.Glu41Lys	missense_variant	Exon 1 of 2		NP_001288662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
COA6	ENST00000366615.10 link	c.349G>A	p.Glu117Lys	missense_variant	Exon 2 of 3	1	NM_001206641.3	ENSP00000355574.5
COA6	ENST00000366613.1 link	c.259G>A	p.Glu87Lys	missense_variant	Exon 2 of 3	1		ENSP00000355572.1
COA6	ENST00000366612.1 link	c.121G>A	p.Glu41Lys	missense_variant	Exon 1 of 2	1		ENSP00000355571.1
COA6	ENST00000619305.1 link	c.121G>A	p.Glu41Lys	missense_variant	Exon 2 of 3	1		ENSP00000479686.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111988

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41398

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

.;.;D;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.88

D;D;D;.

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.48

T;T;T;T

MetaSVM

Uncertain

-0.0059

MutationAssessor

Uncertain

2.2

.;.;M;.

PhyloP100

4.9

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.1

D;.;D;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.015

D;.;D;D

Sift4G

Uncertain

0.040

D;T;T;T

Polyphen

0.95

.;.;P;.

Vest4

0.45

MutPred

0.40

.;.;Gain of MoRF binding (P = 0.0025);.;

MVP

0.89

MPC

1.1

ClinPred

0.99

GERP RS

5.0

Varity_R

0.65

gMVP

0.69

Mutation Taster

=52/48

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over