6-15637804-CCT-AGA

Variant names:

• chr6-15637804-CCT-AGA
• NM_032122.5:c.162-2_162delAGGinsTCT
• DTNBP1 p.Arg54Ser

Variant summary

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

The NM_032122.5(DTNBP1):​c.162-2_162delAGGinsTCT​(p.Arg54Ser) variant causes a splice acceptor, missense, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R54R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DTNBP1 NM_032122.5 splice_acceptor, missense, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.59
• 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: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.057765152 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4, offset of 30, new splice context is: acatgggctgcacttcacAGaag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

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.162-2_162delAGGinsTCT	p.Arg54Ser	splice_acceptor missense splice_region intron	N/A	NP_115498.2
	DTNBP1	NM_001271667.2		c.-82-2_-82delAGGinsTCT		splice_region	Exon 4 of 10	NP_001258596.1	Q96EV8-3
	DTNBP1	NM_001271668.2		c.111-2_111delAGGinsTCT	p.Arg37Ser	splice_acceptor missense splice_region intron	N/A	NP_001258597.1	A6NFV8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNBP1	ENST00000344537.10	TSL:1 MANE Select	c.162-2_162delAGGinsTCT	p.Arg54Ser	splice_acceptor missense splice_region intron	N/A	ENSP00000341680.6	Q96EV8-1
	DTNBP1	ENST00000622898.4	TSL:1	c.57-2_57delAGGinsTCT	p.20	splice_acceptor splice_region synonymous intron	N/A	ENSP00000481997.1	A0A087WYP9
	DTNBP1	ENST00000338950.9	TSL:1	c.162-2_162delAGGinsTCT	p.Arg54Ser	splice_acceptor missense splice_region intron	N/A	ENSP00000344718.5	Q96EV8-2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr6-15638035;