chr12-45050539-T-C

Position:

• chr12-45050539-T-C

Variant summary

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

The NM_001004329.3(DBX2):​c.389A>G​(p.Gln130Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000428 in 1,400,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: DBX2 NM_001004329.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76

Genes affected

DBX2 (HGNC:33186): (developing brain homeobox 2) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

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=0.20013633).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DBX2	NM_001004329.3	c.389A>G	p.Gln130Arg	missense_variant	1/4	ENST00000332700.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBX2	ENST00000332700.6	c.389A>G	p.Gln130Arg	missense_variant	1/4	2	NM_001004329.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000428 AC: 6 AN: 1400252 Hom.: 0 Cov.: 33 AF XY: 0.00000723 AC XY: 5 AN XY: 691140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000277

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: 0.00000463

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000227

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 23, 2024

The c.389A>G (p.Q130R) alteration is located in exon 1 (coding exon 1) of the DBX2 gene. This alteration results from a A to G substitution at nucleotide position 389, causing the glutamine (Q) at amino acid position 130 to be replaced by an arginine (R). 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	Benign	0.082
BayesDel_addAF	Benign	-0.0016	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.98	N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.15
Sift	Benign	0.15	T
Sift4G	Benign	0.70	T
Polyphen		0.24	B
Vest4		0.34
MutPred		0.21		Gain of methylation at Q130 (P = 0.0453);
MVP		0.52
MPC		0.16
ClinPred		0.17	T
GERP RS		2.0
Varity_R		0.097
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs987181390; hg19: chr12-45444322;