20-45406590-C-T

Position:

• chr20-45406590-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001048223.3(DBNDD2):​c.-151C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000184 in 1,304,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: DBNDD2 NM_001048223.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.660

Genes affected

DBNDD2 (HGNC:15881): (dysbindin domain containing 2) Involved in negative regulation of protein kinase activity. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SYS1-DBNDD2 (HGNC:33535): (SYS1-DBNDD2 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription from the neighboring SYS1 Golgi-localized integral membrane protein homolog and dysbindin domain containing 2 (DBNDD2) genes. The read-through transcript includes the majority of exons from each individual gene, but it would be subject to nonsense-mediated mRNA decay (NMD) and is therefore predicted to be non-coding. [provided by RefSeq, Oct 2010]

TP53TG5 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1262275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DBNDD2	NM_001048223.3	c.-151C>T		5_prime_UTR_premature_start_codon_gain_variant	1/4		NP_001041688.1
DBNDD2	NM_001048224.3	c.-151C>T		5_prime_UTR_premature_start_codon_gain_variant	1/4		NP_001041689.1
DBNDD2	NM_018478.3	c.139C>T	p.Arg47Cys	missense_variant	1/4		NP_060948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYS1-DBNDD2	ENST00000458187.5	n.293-1870C>T		intron_variant		5		ENSP00000457768.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000184 AC: 24 AN: 1304082 Hom.: 0 Cov.: 31 AF XY: 0.0000157 AC XY: 10 AN XY: 636670

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000194

Gnomad4 OTH exome AF: 0.0000746

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2023

The c.139C>T (p.R47C) alteration is located in exon 1 (coding exon 1) of the DBNDD2 gene. This alteration results from a C to T substitution at nucleotide position 139, causing the arginine (R) at amino acid position 47 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Benign	0.028
Eigen_PC	Benign	0.087
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.038	D
Vest4		0.14
MutPred		0.24		Gain of catalytic residue at P46 (P = 0.0279);
MVP		0.50
ClinPred		0.49	T
GERP RS		2.9
Varity_R		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs573669747; hg19: chr20-44035230;