rs78457562

Variant names:

• chr20-63930841-C-T
• rs78457562
• NM_025219.3:c.322-10C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025219.3(DNAJC5):​c.322-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0725 in 1,612,042 control chromosomes in the GnomAD database, including 4,963 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (532 hom., cov: 33)
  • Exomes 𝑓: 0.072 (4431 hom.)
• Consequence: DNAJC5 NM_025219.3 intron
• Scores: Splicing: ADA: 0.00001350
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.529
• Publications: 3 publications found

Genes affected

DNAJC5 (HGNC:16235): (DnaJ heat shock protein family (Hsp40) member C5) This gene is a member of the J protein family. J proteins function in many cellular processes by regulating the ATPase activity of 70 kDa heat shock proteins. The encoded protein plays a role in membrane trafficking and protein folding, and has been shown to have anti-neurodegenerative properties. The encoded protein is known to play a role in cystic fibrosis and Huntington's disease. A pseudogene of this gene is located on the short arm of chromosome 8. [provided by RefSeq, Nov 2010]

DNAJC5 Gene-Disease associations (from GenCC):

• ceroid lipofuscinosis, neuronal, 4 (Kufs type)

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• adult neuronal ceroid lipofuscinosis

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-63930841-C-T is Benign according to our data. Variant chr20-63930841-C-T is described in ClinVar as Benign. ClinVar VariationId is 137124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC5	NM_025219.3	c.322-10C>T		intron_variant	Intron 3 of 4	ENST00000360864.9	NP_079495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJC5	ENST00000360864.9	c.322-10C>T		intron_variant	Intron 3 of 4	1	NM_025219.3	ENSP00000354111.4
DNAJC5	ENST00000470551.1	n.322-10C>T		intron_variant	Intron 3 of 5	2		ENSP00000434744.1
DNAJC5	ENST00000703637.1	n.322-10C>T		intron_variant	Intron 3 of 5			ENSP00000515413.1

Frequencies

GnomAD3 genomes AF: 0.0744 AC: 11319 AN: 152200 Hom.: 528 Cov.: 33

Gnomad AFR AF: 0.0680

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0472

Gnomad ASJ AF: 0.0464

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.0343

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0792

Gnomad OTH AF: 0.0651

GnomAD2 exomes AF: 0.0654 AC: 16368 AN: 250390 AF XY: 0.0641

Gnomad AFR exome AF: 0.0668

Gnomad AMR exome AF: 0.0315

Gnomad ASJ exome AF: 0.0432

Gnomad EAS exome AF: 0.00180

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.0731

Gnomad OTH exome AF: 0.0673

GnomAD4 exome AF: 0.0723 AC: 105498 AN: 1459724 Hom.: 4431 Cov.: 32 AF XY: 0.0714 AC XY: 51875 AN XY: 726160

African (AFR) AF: 0.0705 AC: 2355 AN: 33422

American (AMR) AF: 0.0320 AC: 1432 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0445 AC: 1162 AN: 26128

East Asian (EAS) AF: 0.00242 AC: 96 AN: 39700

South Asian (SAS) AF: 0.0408 AC: 3513 AN: 86180

European-Finnish (FIN) AF: 0.175 AC: 9251 AN: 52920

Middle Eastern (MID) AF: 0.0294 AC: 135 AN: 4586

European-Non Finnish (NFE) AF: 0.0751 AC: 83451 AN: 1111836

Other (OTH) AF: 0.0681 AC: 4103 AN: 60238

GnomAD4 genome AF: 0.0745 AC: 11344 AN: 152318 Hom.: 532 Cov.: 33 AF XY: 0.0775 AC XY: 5770 AN XY: 74478

African (AFR) AF: 0.0685 AC: 2850 AN: 41576

American (AMR) AF: 0.0470 AC: 719 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 161 AN: 3472

East Asian (EAS) AF: 0.00328 AC: 17 AN: 5190

South Asian (SAS) AF: 0.0340 AC: 164 AN: 4830

European-Finnish (FIN) AF: 0.175 AC: 1851 AN: 10604

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0792 AC: 5387 AN: 68026

Other (OTH) AF: 0.0653 AC: 138 AN: 2112

Alfa AF: 0.0749 Hom.: 137

Bravo AF: 0.0635

Asia WGS AF: 0.0370 AC: 129 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 05, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Ceroid lipofuscinosis, neuronal, 4 (Kufs type) Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Neuronal ceroid lipofuscinosis Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronal Ceroid-Lipofuscinosis, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.63
DANN	Benign	0.56
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0
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: rs78457562; hg19: chr20-62562194;