rs2283124

Variant names:

• chr9-133650208-C-T
• rs2283124
• NM_000787.4:c.1192-1426C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000787.4(DBH):​c.1192-1426C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 152,110 control chromosomes in the GnomAD database, including 1,429 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1429 hom., cov: 32)
• Consequence: DBH NM_000787.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35
• Publications: 5 publications found

Genes affected

DBH (HGNC:2689): (dopamine beta-hydroxylase) The protein encoded by this gene is an oxidoreductase belonging to the copper type II, ascorbate-dependent monooxygenase family. The encoded protein, expressed in neuroscretory vesicles and chromaffin granules of the adrenal medulla, catalyzes the conversion of dopamine to norepinephrine, which functions as both a hormone and as the main neurotransmitter of the sympathetic nervous system. The enzyme encoded by this gene exists exists in both soluble and membrane-bound forms, depending on the absence or presence, respectively, of a signal peptide. Mutations in this gene cause dopamine beta-hydroxylate deficiency in human patients, characterized by deficits in autonomic and cardiovascular function, including hypotension and ptosis. Polymorphisms in this gene may play a role in a variety of psychiatric disorders. [provided by RefSeq, Aug 2017]

DBH Gene-Disease associations (from GenCC):

• orthostatic hypotension 1

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DBH	NM_000787.4	c.1192-1426C>T		intron_variant	Intron 6 of 11	ENST00000393056.8	NP_000778.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DBH	ENST00000393056.8	c.1192-1426C>T		intron_variant	Intron 6 of 11	1	NM_000787.4	ENSP00000376776.2

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19854 AN: 151992 Hom.: 1425 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.0810

Gnomad ASJ AF: 0.0839

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.0718

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.110

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

GnomAD4 genome AF: 0.131 AC: 19880 AN: 152110 Hom.: 1429 Cov.: 32 AF XY: 0.129 AC XY: 9609 AN XY: 74352

African (AFR) AF: 0.186 AC: 7727 AN: 41508

American (AMR) AF: 0.0808 AC: 1236 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0839 AC: 291 AN: 3470

East Asian (EAS) AF: 0.130 AC: 667 AN: 5146

South Asian (SAS) AF: 0.210 AC: 1012 AN: 4814

European-Finnish (FIN) AF: 0.0718 AC: 761 AN: 10598

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7753 AN: 67954

Other (OTH) AF: 0.109 AC: 231 AN: 2112

Alfa AF: 0.118 Hom.: 1839

Bravo AF: 0.132

Asia WGS AF: 0.168 AC: 584 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.0
DANN	Benign	0.81
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2283124; hg19: chr9-136515330;