20-63929348-C-T

Variant names:

• chr20-63929348-C-T
• rs113987077
• NM_025219.3:c.144C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_025219.3(DNAJC5):​c.144C>T​(p.Pro48Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00846 in 1,614,020 control chromosomes in the GnomAD database, including 1,180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (147 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (1033 hom.)
• Consequence: DNAJC5 NM_025219.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.856
• Publications: 4 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: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• adult neuronal ceroid lipofuscinosis

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 20-63929348-C-T is Benign according to our data. Variant chr20-63929348-C-T is described in ClinVar as Benign. ClinVar VariationId is 196527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.856 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025219.3. 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
	DNAJC5	NM_025219.3	MANE Select	c.144C>T	p.Pro48Pro	synonymous	Exon 3 of 5	NP_079495.1	Q9H3Z4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC5	ENST00000360864.9	TSL:1 MANE Select	c.144C>T	p.Pro48Pro	synonymous	Exon 3 of 5	ENSP00000354111.4	Q9H3Z4-1
	DNAJC5	ENST00000898575.1		c.144C>T	p.Pro48Pro	synonymous	Exon 3 of 5	ENSP00000568634.1
	DNAJC5	ENST00000898576.1		c.144C>T	p.Pro48Pro	synonymous	Exon 3 of 5	ENSP00000568635.1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2150 AN: 152174 Hom.: 147 Cov.: 32

Gnomad AFR AF: 0.00381

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0372

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0326 AC: 8181 AN: 250880 AF XY: 0.0252

Gnomad AFR exome AF: 0.00358

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0382

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000520

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.00787 AC: 11501 AN: 1461728 Hom.: 1033 Cov.: 32 AF XY: 0.00684 AC XY: 4976 AN XY: 727164

African (AFR) AF: 0.00245 AC: 82 AN: 33480

American (AMR) AF: 0.195 AC: 8684 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0362 AC: 1438 AN: 39700

South Asian (SAS) AF: 0.00342 AC: 295 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53362

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.000469 AC: 521 AN: 1111994

Other (OTH) AF: 0.00777 AC: 469 AN: 60392

GnomAD4 genome AF: 0.0141 AC: 2147 AN: 152292 Hom.: 147 Cov.: 32 AF XY: 0.0158 AC XY: 1180 AN XY: 74470

African (AFR) AF: 0.00380 AC: 158 AN: 41578

American (AMR) AF: 0.111 AC: 1699 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0369 AC: 191 AN: 5172

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68028

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.00266 Hom.: 4

Bravo AF: 0.0241

Asia WGS AF: 0.0220 AC: 76 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000949

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Ceroid lipofuscinosis, neuronal, 4 (Kufs type) (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuronal ceroid lipofuscinosis (1)
-	-	1	Neuronal Ceroid-Lipofuscinosis, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.8
DANN	Benign	0.79
PhyloP100		-0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs113987077; hg19: chr20-62560701; COSMIC: COSV62671797;