chr7-103313101-C-A
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_014377.3(DNAJC2):c.1637G>T(p.Gly546Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000401 in 1,597,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000042 ( 0 hom. )
Consequence
DNAJC2
NM_014377.3 missense, splice_region
NM_014377.3 missense, splice_region
Scores
4
13
Splicing: ADA: 0.8887
1
1
Clinical Significance
Conservation
PhyloP100: 1.68
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAJC2 | NM_014377.3 | c.1637G>T | p.Gly546Val | missense_variant, splice_region_variant | 16/17 | ENST00000379263.8 | |
PMPCB | NM_004279.3 | c.*830C>A | 3_prime_UTR_variant | 13/13 | ENST00000249269.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAJC2 | ENST00000379263.8 | c.1637G>T | p.Gly546Val | missense_variant, splice_region_variant | 16/17 | 1 | NM_014377.3 | P1 | |
PMPCB | ENST00000249269.9 | c.*830C>A | 3_prime_UTR_variant | 13/13 | 1 | NM_004279.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152076Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000116 AC: 27AN: 233316Hom.: 0 AF XY: 0.000118 AC XY: 15AN XY: 126794
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GnomAD4 exome AF: 0.0000422 AC: 61AN: 1445124Hom.: 0 Cov.: 32 AF XY: 0.0000445 AC XY: 32AN XY: 718612
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152076Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74272
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 15, 2023 | The c.1637G>T (p.G546V) alteration is located in exon 16 (coding exon 16) of the DNAJC2 gene. This alteration results from a G to T substitution at nucleotide position 1637, causing the glycine (G) at amino acid position 546 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;D
Sift4G
Uncertain
D;D
Polyphen
B;B
Vest4
MVP
MPC
0.31
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -12
Find out detailed SpliceAI scores and Pangolin per-transcript scores at