10-67797180-C-G

Variant names:

• chr10-67797180-C-G
• rs764261610
• NM_021800.3:c.533G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021800.3(DNAJC12):​c.533G>C​(p.Arg178Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,378 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNAJC12 NM_021800.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.14

Genes affected

DNAJC12 (HGNC:28908): (DnaJ heat shock protein family (Hsp40) member C12) This gene encodes a member of a subclass of the HSP40/DnaJ protein family. Members of this family of proteins are associated with complex assembly, protein folding, and export. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

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 rank	MANE	Protein	UniProt
DNAJC12	NM_021800.3	c.533G>C	p.Arg178Pro	missense_variant	Exon 5 of 5	ENST00000225171.7	NP_068572.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJC12	ENST00000225171.7	c.533G>C	p.Arg178Pro	missense_variant	Exon 5 of 5	1	NM_021800.3	ENSP00000225171.2
DNAJC12	ENST00000483798.6	c.623G>C	p.Arg208Pro	missense_variant	Exon 6 of 6	3		ENSP00000474215.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461378 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726946

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.533G>C (p.R178P) alteration is located in exon 5 (coding exon 5) of the DNAJC12 gene. This alteration results from a G to C substitution at nucleotide position 533, causing the arginine (R) at amino acid position 178 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.094	T;.
Eigen	Benign	0.073
Eigen_PC	Benign	0.010
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	2.9	M;.
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.1	D;.
REVEL	Benign	0.19
Sift	Benign	0.070	T;.
Sift4G	Benign	0.080	T;T
Polyphen		0.93	P;.
Vest4		0.65
MutPred		0.46		Loss of MoRF binding (P = 0.0028);.;
MVP		0.42
MPC		0.37
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.64
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs764261610; hg19: chr10-69556938;