2-182720007-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018981.4(DNAJC10):c.205A>C(p.Asn69His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: DNAJC10 NM_018981.4 missense, splice_region
• Scores: Splicing: ADA: 0.8025
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.11

Genes affected

DNAJC10 (HGNC:24637): (DnaJ heat shock protein family (Hsp40) member C10) This gene encodes an endoplasmic reticulum co-chaperone which is part of the endoplasmic reticulum-associated degradation complex involved in recognizing and degrading misfolded proteins. The encoded protein reduces incorrect disulfide bonds in misfolded glycoproteins. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37266955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJC10	NM_018981.4	c.205A>C	p.Asn69His	missense_variant, splice_region_variant	4/24	ENST00000264065.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJC10	ENST00000264065.12	c.205A>C	p.Asn69His	missense_variant, splice_region_variant	4/24	1	NM_018981.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2021

The c.205A>C (p.N69H) alteration is located in exon 4 (coding exon 2) of the DNAJC10 gene. This alteration results from a A to C substitution at nucleotide position 205, causing the asparagine (N) at amino acid position 69 to be replaced by a histidine (H). 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	0.10
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.37	T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.67	N;N;.;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
Sift4G	Uncertain	0.027	D;D;.;D;D
Polyphen		0.98	D;D;.;.;.
Vest4		0.39
MutPred		0.44		Gain of catalytic residue at N70 (P = 0.1296);Gain of catalytic residue at N70 (P = 0.1296);Gain of catalytic residue at N70 (P = 0.1296);Gain of catalytic residue at N70 (P = 0.1296);Gain of catalytic residue at N70 (P = 0.1296);
MVP		0.86
MPC		0.10
ClinPred		0.75	D
GERP RS		5.7
Varity_R		0.19
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.80
dbscSNV1_RF	Benign	0.52
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-183584734;