rs2056943

Variant names:

• chr6-15524332-T-C
• rs2056943
• ENST00000338950.9:c.*93A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_183040.2(DTNBP1):​c.*93A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0375 in 1,611,786 control chromosomes in the GnomAD database, including 1,222 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (85 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1137 hom.)
• Consequence: DTNBP1 NM_183040.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.551
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-15524332-T-C is Benign according to our data. Variant chr6-15524332-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1214828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0293 (4462/152202) while in subpopulation NFE AF = 0.0456 (3101/68004). AF 95% confidence interval is 0.0443. There are 85 homozygotes in GnomAd4. There are 2122 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 85 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183040.2. 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.811+194A>G		intron	N/A	NP_115498.2
	DTNBP1	NM_183040.2		c.*93A>G		3_prime_UTR	Exon 9 of 9	NP_898861.1	Q96EV8-2
	DTNBP1	NM_001271668.2		c.760+194A>G		intron	N/A	NP_001258597.1	A6NFV8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNBP1	ENST00000338950.9	TSL:1	c.*93A>G		3_prime_UTR	Exon 9 of 9	ENSP00000344718.5	Q96EV8-2
	DTNBP1	ENST00000344537.10	TSL:1 MANE Select	c.811+194A>G		intron	N/A	ENSP00000341680.6	Q96EV8-1
	DTNBP1	ENST00000622898.4	TSL:1	c.706+194A>G		intron	N/A	ENSP00000481997.1	A0A087WYP9

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4467 AN: 152084 Hom.: 85 Cov.: 33

Gnomad AFR AF: 0.00708

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0296

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0350

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0456

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0311 AC: 7824 AN: 251420 AF XY: 0.0311

Gnomad AFR exome AF: 0.00683

Gnomad AMR exome AF: 0.0198

Gnomad ASJ exome AF: 0.0342

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0400

Gnomad NFE exome AF: 0.0451

Gnomad OTH exome AF: 0.0344

GnomAD4 exome AF: 0.0384 AC: 56041 AN: 1459584 Hom.: 1137 Cov.: 35 AF XY: 0.0380 AC XY: 27596 AN XY: 726122

African (AFR) AF: 0.00634 AC: 212 AN: 33438

American (AMR) AF: 0.0207 AC: 927 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0341 AC: 892 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39674

South Asian (SAS) AF: 0.0152 AC: 1304 AN: 85540

European-Finnish (FIN) AF: 0.0410 AC: 2187 AN: 53354

Middle Eastern (MID) AF: 0.0227 AC: 108 AN: 4756

European-Non Finnish (NFE) AF: 0.0434 AC: 48268 AN: 1111724

Other (OTH) AF: 0.0355 AC: 2141 AN: 60262

GnomAD4 genome AF: 0.0293 AC: 4462 AN: 152202 Hom.: 85 Cov.: 33 AF XY: 0.0285 AC XY: 2122 AN XY: 74426

African (AFR) AF: 0.00706 AC: 293 AN: 41518

American (AMR) AF: 0.0295 AC: 451 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 104 AN: 3462

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4824

European-Finnish (FIN) AF: 0.0350 AC: 372 AN: 10614

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0456 AC: 3101 AN: 68004

Other (OTH) AF: 0.0298 AC: 63 AN: 2112

Alfa AF: 0.0391 Hom.: 252

Bravo AF: 0.0270

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.86
DANN	Benign	0.74
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

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: rs2056943; hg19: chr6-15524563;