7-103315776-C-T

Variant names:

• chr7-103315776-C-T
• rs751977267
• NM_014377.3:c.1624G>A

Variant summary

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

The NM_014377.3(DNAJC2):​c.1624G>A​(p.Glu542Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,460,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E542G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: DNAJC2 NM_014377.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.54
• Publications: 0 publications found

Genes affected

DNAJC2 (HGNC:13192): (DnaJ heat shock protein family (Hsp40) member C2) This gene is a member of the M-phase phosphoprotein (MPP) family. The gene encodes a phosphoprotein with a J domain and a Myb DNA-binding domain which localizes to both the nucleus and the cytosol. The protein is capable of forming a heterodimeric complex that associates with ribosomes, acting as a molecular chaperone for nascent polypeptide chains as they exit the ribosome. This protein was identified as a leukemia-associated antigen and expression of the gene is upregulated in leukemic blasts. Also, chromosomal aberrations involving this gene are associated with primary head and neck squamous cell tumors. This gene has a pseudogene on chromosome 6. Alternatively spliced variants which encode different protein isoforms have been described. [provided by RefSeq, Jul 2008]

PMPCB (HGNC:9119): (peptidase, mitochondrial processing subunit beta) This gene is a member of the peptidase M16 family and encodes a protein with a zinc-binding motif. This protein is located in the mitochondrial matrix and catalyzes the cleavage of the leader peptides of precursor proteins newly imported into the mitochondria, though it only functions as part of a heterodimeric complex. [provided by RefSeq, Jul 2008]

PMPCB Gene-Disease associations (from GenCC):

• multiple mitochondrial dysfunctions syndrome 6

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

ENSG00000289613 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014377.3. 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
	DNAJC2	NM_014377.3	MANE Select	c.1624G>A	p.Glu542Lys	missense	Exon 15 of 17	NP_055192.1	Q99543-1
	DNAJC2	NM_001129887.3		c.1465G>A	p.Glu489Lys	missense	Exon 13 of 15	NP_001123359.1	Q99543-2
	DNAJC2	NM_001362667.2		c.1402G>A	p.Glu468Lys	missense	Exon 15 of 17	NP_001349596.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC2	ENST00000379263.8	TSL:1 MANE Select	c.1624G>A	p.Glu542Lys	missense	Exon 15 of 17	ENSP00000368565.3	Q99543-1
	DNAJC2	ENST00000249270.11	TSL:1	c.1465G>A	p.Glu489Lys	missense	Exon 13 of 15	ENSP00000249270.7	Q99543-2
	DNAJC2	ENST00000464253.5	TSL:1	n.1567G>A		non_coding_transcript_exon	Exon 14 of 16

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 249182 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1460808 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 726756

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111188

Other (OTH) AF: 0.0000331 AC: 2 AN: 60356

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	Uncertain	0.37
BayesDel_addAF	Benign	-0.0098	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.036	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.5
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.34
Sift	Benign	0.084	T
Sift4G	Benign	0.21	T
Polyphen		1.0	D
Vest4		0.73
MutPred		0.33		Gain of ubiquitination at E542 (P = 0.0045)
MVP		0.60
MPC		0.50
ClinPred		0.32	T
GERP RS		5.8
Varity_R		0.22
gMVP		0.51
Mutation Taster		=19/81	disease causing

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

dbSNP: rs751977267; hg19: chr7-102956223;