chr2-182736296-C-A

Variant names:

• chr2-182736296-C-A
• rs764589408
• NM_018981.4:c.897C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018981.4(DNAJC10):​c.897C>A​(p.Asn299Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000251 in 1,594,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DNAJC10 NM_018981.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.539
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062030524).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018981.4. 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
	DNAJC10	NM_018981.4	MANE Select	c.897C>A	p.Asn299Lys	missense	Exon 11 of 24	NP_061854.1	Q8IXB1-1
	DNAJC10	NM_001271581.3		c.849+3754C>A		intron	N/A	NP_001258510.1	Q8IXB1-2
	DNAJC10	NR_073365.2		n.1327C>A		non_coding_transcript_exon	Exon 11 of 24

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC10	ENST00000264065.12	TSL:1 MANE Select	c.897C>A	p.Asn299Lys	missense	Exon 11 of 24	ENSP00000264065.6	Q8IXB1-1
	DNAJC10	ENST00000537515.5	TSL:1	c.897C>A	p.Asn299Lys	missense	Exon 9 of 10	ENSP00000441560.1	Q8IXB1-3
	DNAJC10	ENST00000616986.5	TSL:1	c.849+3754C>A		intron	N/A	ENSP00000479930.1	Q8IXB1-2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1441986 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 716994

African (AFR) AF: 0.0000624 AC: 2 AN: 32056

American (AMR) AF: 0.00 AC: 0 AN: 40780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25794

East Asian (EAS) AF: 0.00 AC: 0 AN: 37870

South Asian (SAS) AF: 0.00 AC: 0 AN: 82280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104770

Other (OTH) AF: 0.00 AC: 0 AN: 59570

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74298

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

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	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Benign	0.87
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.54
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.034
Sift	Benign	0.72	T
Sift4G	Benign	0.90	T
Polyphen		0.0050	B
Vest4		0.17
MutPred		0.39		Gain of ubiquitination at N299 (P = 0.0325)
MVP		0.32
MPC		0.076
ClinPred		0.18	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.055
gMVP		0.48
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs764589408; hg19: chr2-183601023;