rs4850

Positions:

• chr16-21965441-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

The NM_003366.4(UQCRC2):​c.548G>A​(p.Arg183Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0469 in 1,613,620 control chromosomes in the GnomAD database, including 2,191 homozygotes. In-silico tool predicts 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. R183W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.037 (156 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2035 hom.)
• Consequence: UQCRC2 NM_003366.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.79

Genes affected

UQCRC2 (HGNC:12586): (ubiquinol-cytochrome c reductase core protein 2) The protein encoded by this gene is located in the mitochondrion, where it is part of the ubiquinol-cytochrome c reductase complex (also known as complex III). This complex constitutes a part of the mitochondrial respiratory chain. Defects in this gene are a cause of mitochondrial complex III deficiency nuclear type 5. [provided by RefSeq, Jul 2015]

PDZD9 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-21965440-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 41880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0042624474).
• BP6: Variant 16-21965441-G-A is Benign according to our data. Variant chr16-21965441-G-A is described in ClinVar as [Benign]. Clinvar id is 380582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-21965441-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UQCRC2	NM_003366.4	c.548G>A	p.Arg183Gln	missense_variant	7/14	ENST00000268379.9
PDZD9	XM_017023109.2	c.607-7824C>T		intron_variant
PDZD9	XM_047433888.1	c.601-7824C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UQCRC2	ENST00000268379.9	c.548G>A	p.Arg183Gln	missense_variant	7/14	1	NM_003366.4	P1

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 5605 AN: 152076 Hom.: 157 Cov.: 32

Gnomad AFR AF: 0.00985

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0319

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00993

Gnomad FIN AF: 0.0548

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.0568

Gnomad OTH AF: 0.0278

GnomAD3 exomes AF: 0.0393 AC: 9863 AN: 250954 Hom.: 273 AF XY: 0.0394 AC XY: 5349 AN XY: 135630

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.0181

Gnomad ASJ exome AF: 0.0283

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0125

Gnomad FIN exome AF: 0.0535

Gnomad NFE exome AF: 0.0615

Gnomad OTH exome AF: 0.0437

GnomAD4 exome AF: 0.0480 AC: 70150 AN: 1461424 Hom.: 2035 Cov.: 30 AF XY: 0.0473 AC XY: 34384 AN XY: 727034

Gnomad4 AFR exome AF: 0.00828

Gnomad4 AMR exome AF: 0.0191

Gnomad4 ASJ exome AF: 0.0280

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0130

Gnomad4 FIN exome AF: 0.0580

Gnomad4 NFE exome AF: 0.0553

Gnomad4 OTH exome AF: 0.0395

GnomAD4 genome AF: 0.0368 AC: 5602 AN: 152196 Hom.: 156 Cov.: 32 AF XY: 0.0364 AC XY: 2711 AN XY: 74410

Gnomad4 AFR AF: 0.00982

Gnomad4 AMR AF: 0.0319

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00993

Gnomad4 FIN AF: 0.0548

Gnomad4 NFE AF: 0.0568

Gnomad4 OTH AF: 0.0275

Alfa AF: 0.0494 Hom.: 370

Bravo AF: 0.0341

TwinsUK AF: 0.0518 AC: 192

ALSPAC AF: 0.0522 AC: 201

ESP6500AA AF: 0.0118 AC: 52

ESP6500EA AF: 0.0537 AC: 462

ExAC AF: 0.0429 AC: 5207

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 12, 2016

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. -

Mitochondrial complex III deficiency nuclear type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.76	D
MetaRNN	Benign	0.0043	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	0.89	D;D
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Benign	0.085
Sift	Uncertain	0.024	D;D;D
Sift4G	Benign	0.074	T;T;T
Polyphen		0.59	P;.;.
Vest4		0.061
MPC		0.48
ClinPred		0.026	T
GERP RS		1.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.36
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs4850; hg19: chr16-21976762;