2-182728972-T-C

Variant names:

• chr2-182728972-T-C
• rs1191402715
• NM_018981.4:c.611T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_018981.4(DNAJC10):​c.611T>C​(p.Leu204Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L204H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAJC10 NM_018981.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.59
• Publications: 1 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

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.611T>C	p.Leu204Pro	missense	Exon 7 of 24	NP_061854.1	Q8IXB1-1
	DNAJC10	NM_001271581.3		c.611T>C	p.Leu204Pro	missense	Exon 7 of 23	NP_001258510.1	Q8IXB1-2
	DNAJC10	NR_073365.2		n.1041T>C		non_coding_transcript_exon	Exon 7 of 24

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC10	ENST00000264065.12	TSL:1 MANE Select	c.611T>C	p.Leu204Pro	missense	Exon 7 of 24	ENSP00000264065.6	Q8IXB1-1
	DNAJC10	ENST00000616986.5	TSL:1	c.611T>C	p.Leu204Pro	missense	Exon 7 of 23	ENSP00000479930.1	Q8IXB1-2
	DNAJC10	ENST00000537515.5	TSL:1	c.611T>C	p.Leu204Pro	missense	Exon 5 of 10	ENSP00000441560.1	Q8IXB1-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.89		Loss of stability (P = 0.0123)
MVP		0.93
MPC		0.49
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.93
gMVP		0.99
Mutation Taster		=3/97	disease causing

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

Other links and lift over

dbSNP: rs1191402715; hg19: chr2-183593699;