2-182759174-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_018981.4(DNAJC10):c.2012T>C(p.Val671Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,429,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: DNAJC10 NM_018981.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.17

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04986453).
• BP6: Variant 2-182759174-T-C is Benign according to our data. Variant chr2-182759174-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3084439.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJC10	NM_018981.4	c.2012T>C	p.Val671Ala	missense_variant	21/24	ENST00000264065.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJC10	ENST00000264065.12	c.2012T>C	p.Val671Ala	missense_variant	21/24	1	NM_018981.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000407 AC: 9 AN: 221152 Hom.: 0 AF XY: 0.0000416 AC XY: 5 AN XY: 120102

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000851

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000168 AC: 24 AN: 1429726 Hom.: 0 Cov.: 30 AF XY: 0.0000169 AC XY: 12 AN XY: 710660

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: 0.0000188

Gnomad4 NFE exome AF: 0.0000172

Gnomad4 OTH exome AF: 0.0000677

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	14
Dann	Benign	0.90
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.76	D
PrimateAI	Benign	0.32	T
Sift4G	Benign	0.77	T;T
Polyphen		0.0	B;B
Vest4		0.17
MutPred		0.53		.;Gain of disorder (P = 0.0312);
MVP		0.34
MPC		0.076
ClinPred		0.023	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.52

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: rs754566665; hg19: chr2-183623901;