chr6-15523010-CCT-C

Variant names:

• chr6-15523010-CCT-C
• rs752074481
• NM_032122.5:c.1019_1020delAG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_032122.5(DTNBP1):​c.1019_1020delAG​(p.Glu340GlyfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 1,614,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: DTNBP1 NM_032122.5 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.23
• Publications: 0 publications found

Genes affected

DTNBP1 (HGNC:17328): (dystrobrevin binding protein 1) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. A similar protein in mouse is a component of a protein complex termed biogenesis of lysosome-related organelles complex 1 (BLOC-1), and binds to alpha- and beta-dystrobrevins, which are components of the dystrophin-associated protein complex (DPC). Mutations in this gene are associated with Hermansky-Pudlak syndrome type 7. This gene may also be associated with schizophrenia. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

DTNBP1 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.035 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032122.5. 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
	DTNBP1	NM_032122.5	MANE Select	c.1019_1020delAG	p.Glu340GlyfsTer7	frameshift	Exon 10 of 10	NP_115498.2
	DTNBP1	NM_001271668.2		c.968_969delAG	p.Glu323GlyfsTer7	frameshift	Exon 9 of 9	NP_001258597.1	A6NFV8
	DTNBP1	NM_001271669.2		c.914_915delAG	p.Glu305GlyfsTer7	frameshift	Exon 8 of 8	NP_001258598.1	A0A087WYP9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNBP1	ENST00000344537.10	TSL:1 MANE Select	c.1019_1020delAG	p.Glu340GlyfsTer7	frameshift	Exon 10 of 10	ENSP00000341680.6	Q96EV8-1
	DTNBP1	ENST00000622898.4	TSL:1	c.914_915delAG	p.Glu305GlyfsTer7	frameshift	Exon 8 of 8	ENSP00000481997.1	A0A087WYP9
	DTNBP1	ENST00000857317.1		c.1100_1101delAG	p.Glu367GlyfsTer7	frameshift	Exon 10 of 10	ENSP00000527376.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000123 AC: 31 AN: 251488 AF XY: 0.000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000650 AC: 95 AN: 1461892 Hom.: 0 AF XY: 0.0000715 AC XY: 52 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1112010

Other (OTH) AF: 0.000182 AC: 11 AN: 60396

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74502

African (AFR) AF: 0.0000481 AC: 2 AN: 41590

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000145 Hom.: 0

Bravo AF: 0.0000945

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	2	-	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=113/87	disease causing (ClinVar)

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: rs752074481; hg19: chr6-15523241; COSMIC: COSV100160747; COSMIC: COSV100160747;