16-57447522-T-C

Variant names:

• chr16-57447522-T-C
• rs1418552732
• NM_020312.4:c.17T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020312.4(COQ9):​c.17T>C​(p.Val6Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000245 in 1,225,144 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V6V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: COQ9 NM_020312.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.811

Genes affected

COQ9 (HGNC:25302): (coenzyme Q9) This locus represents a mitochondrial ubiquinone biosynthesis gene. The encoded protein is likely necessary for biosynthesis of coenzyme Q10, as mutations at this locus have been associated with autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency.[provided by RefSeq, Sep 2010]

CIAPIN1 (HGNC:28050): (cytokine induced apoptosis inhibitor 1) CIAPIN1 is a cytokine-induced inhibitor of apoptosis with no relation to apoptosis regulatory molecules of the BCL2 (MIM 151430) or CASP (see MIM 147678) families. Expression of CIAPIN1 is dependent on growth factor stimulation (Shibayama et al., 2004 [PubMed 14970183]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.081569344).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ9	NM_020312.4	c.17T>C	p.Val6Ala	missense_variant	Exon 1 of 9	ENST00000262507.11	NP_064708.1
CIAPIN1	NM_020313.4	c.-236A>G		upstream_gene_variant		ENST00000394391.9	NP_064709.2
CIAPIN1	NM_001308347.2	c.-236A>G		upstream_gene_variant			NP_001295276.1
CIAPIN1	NM_001308358.2	c.-236A>G		upstream_gene_variant			NP_001295287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COQ9	ENST00000262507.11	c.17T>C	p.Val6Ala	missense_variant	Exon 1 of 9	1	NM_020312.4	ENSP00000262507.5
CIAPIN1	ENST00000394391.9	c.-236A>G		upstream_gene_variant		1	NM_020313.4	ENSP00000377914.4

Frequencies

GnomAD3 genomes AF: 0.00000671 AC: 1 AN: 148986 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1076158 Hom.: 0 Cov.: 32 AF XY: 0.00000385 AC XY: 2 AN XY: 518912

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000220

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000671 AC: 1 AN: 148986 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 1 AN XY: 72716

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 08, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 6 of the COQ9 protein (p.Val6Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COQ9-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.64
DEOGEN2	Benign	0.0049	T;T;T;T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.54	T;T;T;T;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.082	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.89	L;.;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.83	N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.25	T;T;T;T;T
Sift4G	Benign	0.095	T;D;T;T;T
Polyphen		0.0010	B;.;.;.;.
Vest4		0.38
MutPred		0.44		Gain of disorder (P = 0.0174);Gain of disorder (P = 0.0174);Gain of disorder (P = 0.0174);Gain of disorder (P = 0.0174);Gain of disorder (P = 0.0174);
MVP		0.076
MPC		0.19
ClinPred		0.13	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.31

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

Other links and lift over

dbSNP: rs1418552732; hg19: chr16-57481434;