rs4850

Variant names:

• chr16-21965441-G-A
• rs4850
• NM_003366.4:c.548G>A

Variant summary

Our verdict is Benign. The variant received -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. 12/21 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. 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
• Publications: 26 publications found

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:28740): (PDZ domain containing 9)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-21965440-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId 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 VariationId is 380582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0553 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003366.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UQCRC2	NM_003366.4	MANE Select	c.548G>A	p.Arg183Gln	missense	Exon 7 of 14	NP_003357.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UQCRC2	ENST00000268379.9	TSL:1 MANE Select	c.548G>A	p.Arg183Gln	missense	Exon 7 of 14	ENSP00000268379.4
	UQCRC2	ENST00000561553.5	TSL:5	c.548G>A	p.Arg183Gln	missense	Exon 7 of 13	ENSP00000456232.1
	UQCRC2	ENST00000565331.5	TSL:3	c.464G>A	p.Arg155Gln	missense	Exon 6 of 6	ENSP00000455088.1

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

GnomAD2 exomes AF: 0.0393 AC: 9863 AN: 250954 AF XY: 0.0394

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 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

African (AFR) AF: 0.00828 AC: 277 AN: 33468

American (AMR) AF: 0.0191 AC: 855 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 732 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39660

South Asian (SAS) AF: 0.0130 AC: 1118 AN: 86252

European-Finnish (FIN) AF: 0.0580 AC: 3094 AN: 53376

Middle Eastern (MID) AF: 0.0371 AC: 214 AN: 5764

European-Non Finnish (NFE) AF: 0.0553 AC: 61471 AN: 1111706

Other (OTH) AF: 0.0395 AC: 2387 AN: 60366

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

African (AFR) AF: 0.00982 AC: 408 AN: 41532

American (AMR) AF: 0.0319 AC: 487 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00993 AC: 48 AN: 4832

European-Finnish (FIN) AF: 0.0548 AC: 580 AN: 10578

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0568 AC: 3863 AN: 68000

Other (OTH) AF: 0.0275 AC: 58 AN: 2110

Alfa AF: 0.0484 Hom.: 776

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Mitochondrial complex III deficiency nuclear type 5 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.76	D
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.8
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.085
Sift	Uncertain	0.024	D
Sift4G	Benign	0.074	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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4850; hg19: chr16-21976762; COSMIC: COSV107271500; COSMIC: COSV107271500;