Genetic Variant NM_018981.4:c.203C>T (chr2-182718289-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_018981.4(DNAJC10):c.203C>T(p.Pro68Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000697 in 1,433,816 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Consequence

DNAJC10
NM_018981.4 missense, splice_region

Scores

Splicing: ADA: 0.9941

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.21

Publications

1 publications found

Variant links:

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]

DNAJC10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAJC10	NM_018981.4	MANE Select	c.203C>T	p.Pro68Leu	missense splice_region	Exon 3 of 24	NP_061854.1	Q8IXB1-1
DNAJC10	NM_001271581.3		c.203C>T	p.Pro68Leu	missense splice_region	Exon 3 of 23	NP_001258510.1	Q8IXB1-2
DNAJC10	NR_073365.2		n.633C>T		splice_region non_coding_transcript_exon	Exon 3 of 24

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAJC10	ENST00000264065.12	TSL:1 MANE Select	c.203C>T	p.Pro68Leu	missense splice_region	Exon 3 of 24	ENSP00000264065.6	Q8IXB1-1
DNAJC10	ENST00000616986.5	TSL:1	c.203C>T	p.Pro68Leu	missense splice_region	Exon 3 of 23	ENSP00000479930.1	Q8IXB1-2
DNAJC10	ENST00000537515.5	TSL:1	c.203C>T	p.Pro68Leu	missense splice_region	Exon 1 of 10	ENSP00000441560.1	Q8IXB1-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000442

AC:

AN:

226058

AF XY:

0.00000814

show subpopulations

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:

0.00

GnomAD4 exome

AF:

0.00000697

AC:

AN:

1433816

Hom.:

Cov.:

AF XY:

0.00000843

AC XY:

AN XY:

711678

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32318

American (AMR)

AF:

0.00

AC:

AN:

39416

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25070

East Asian (EAS)

AF:

0.00

AC:

AN:

39118

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79264

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52342

Middle Eastern (MID)

AF:

0.000187

AC:

AN:

5334

European-Non Finnish (NFE)

AF:

0.00000363

AC:

AN:

1101646

Other (OTH)

AF:

0.0000674

AC:

AN:

59308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.034

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.4

PhyloP100

3.2

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.39

Sift

Benign

0.051

Sift4G

Benign

0.072

Polyphen

0.97

Vest4

0.19

MutPred

0.56

Loss of methylation at K66 (P = 0.0597)

MVP

0.80

MPC

0.077

ClinPred

0.89

GERP RS

4.6

PromoterAI

-0.010

Neutral

(source)

Varity_R

0.20

gMVP

0.42

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.77

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over