16-21984317-A-C

Variant names:

• chr16-21984317-A-C
• NM_001363519.1:c.745T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001363519.1(PDZD9):​c.745T>G​(p.Cys249Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDZD9 NM_001363519.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13
• Publications: 0 publications found

Genes affected

PDZD9 (HGNC:28740): (PDZ domain containing 9)

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]

UQCRC2 Gene-Disease associations (from GenCC):

• mitochondrial complex III deficiency nuclear type 5

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• mitochondrial complex III deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11643037).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363519.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD9	NM_001363519.1	MANE Select	c.745T>G	p.Cys249Gly	missense	Exon 4 of 4	NP_001350448.1	Q8IXQ8-1
	PDZD9	NM_173806.4		c.565T>G	p.Cys189Gly	missense	Exon 3 of 3	NP_776167.2	Q8IXQ8-3
	PDZD9	NM_001370530.1		c.559T>G	p.Cys187Gly	missense	Exon 5 of 5	NP_001357459.1	Q8IXQ8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD9	ENST00000424898.3	TSL:5 MANE Select	c.745T>G	p.Cys249Gly	missense	Exon 4 of 4	ENSP00000400514.2	Q8IXQ8-1
	PDZD9	ENST00000523914.5	TSL:1	n.*522T>G		non_coding_transcript_exon	Exon 5 of 5	ENSP00000429211.1	E5RJ18
	PDZD9	ENST00000523914.5	TSL:1	n.*522T>G		3_prime_UTR	Exon 5 of 5	ENSP00000429211.1	E5RJ18

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.63	D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.1
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.13
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.020	D
Vest4		0.10
MutPred		0.54		Gain of disorder (P = 0.0149)
MVP		0.26
MPC		0.37
ClinPred		0.77	D
GERP RS		4.2
Varity_R		0.37
gMVP		0.026

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

Other links and lift over

hg19: chr16-21995638;