NM_032122.5:c.662G>A

Variant names:

• chr6-15533245-C-T
• rs76349207
• NM_032122.5:c.662G>A

Variant summary

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

The NM_032122.5(DTNBP1):​c.662G>A​(p.Arg221Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000509 in 1,613,920 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R221G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: DTNBP1 NM_032122.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:2 B:3
• Conservation: PhyloP100: 4.94
• Publications: 3 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), ClinGen, G2P

LOC105374947 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.011042416).
• BP6: Variant 6-15533245-C-T is Benign according to our data. Variant chr6-15533245-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 434963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00199 (303/152256) while in subpopulation AFR AF = 0.00589 (245/41564). AF 95% confidence interval is 0.00529. There are 2 homozygotes in GnomAd4. There are 143 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNBP1	NM_032122.5	MANE Select	c.662G>A	p.Arg221Gln	missense	Exon 8 of 10	NP_115498.2
	DTNBP1	NM_001271668.2		c.611G>A	p.Arg204Gln	missense	Exon 7 of 9	NP_001258597.1
	DTNBP1	NM_001271669.2		c.557G>A	p.Arg186Gln	missense	Exon 6 of 8	NP_001258598.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNBP1	ENST00000344537.10	TSL:1 MANE Select	c.662G>A	p.Arg221Gln	missense	Exon 8 of 10	ENSP00000341680.6
	DTNBP1	ENST00000622898.4	TSL:1	c.557G>A	p.Arg186Gln	missense	Exon 6 of 8	ENSP00000481997.1
	DTNBP1	ENST00000338950.9	TSL:1	c.662G>A	p.Arg221Gln	missense	Exon 8 of 9	ENSP00000344718.5

Frequencies

GnomAD3 genomes AF: 0.00199 AC: 302 AN: 152138 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00589

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000565 AC: 142 AN: 251384 AF XY: 0.000456

Gnomad AFR exome AF: 0.00597

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000354 AC: 518 AN: 1461664 Hom.: 1 Cov.: 32 AF XY: 0.000359 AC XY: 261 AN XY: 727126

African (AFR) AF: 0.00627 AC: 210 AN: 33480

American (AMR) AF: 0.000760 AC: 34 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00213 AC: 12 AN: 5634

European-Non Finnish (NFE) AF: 0.000179 AC: 199 AN: 1112004

Other (OTH) AF: 0.000977 AC: 59 AN: 60376

GnomAD4 genome AF: 0.00199 AC: 303 AN: 152256 Hom.: 2 Cov.: 31 AF XY: 0.00192 AC XY: 143 AN XY: 74434

African (AFR) AF: 0.00589 AC: 245 AN: 41564

American (AMR) AF: 0.00268 AC: 41 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68014

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.000862 Hom.: 0

Bravo AF: 0.00253

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000766 AC: 93

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000474

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2 Benign:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Mar 23, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DTNBP1-related disorder Benign:1

Jun 16, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.26
Sift	Benign	0.063	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.65
MVP		0.76
MPC		0.55
ClinPred		0.047	T
GERP RS		5.5
Varity_R		0.10
gMVP		0.38
Mutation Taster		=90/10	polymorphism

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: rs76349207; hg19: chr6-15533476;