12-45050636-G-C

Position:

• chr12-45050636-G-C

Variant summary

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

The NM_001004329.3(DBX2):​c.292C>G​(p.Pro98Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000501 in 1,397,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: DBX2 NM_001004329.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.46

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DBX2	NM_001004329.3	c.292C>G	p.Pro98Ala	missense_variant	1/4	ENST00000332700.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBX2	ENST00000332700.6	c.292C>G	p.Pro98Ala	missense_variant	1/4	2	NM_001004329.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000501 AC: 7 AN: 1397760 Hom.: 0 Cov.: 33 AF XY: 0.00000580 AC XY: 4 AN XY: 689546

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: 0.00000556

Gnomad4 OTH exome AF: 0.0000173

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

Jun 06, 2023

The c.292C>G (p.P98A) alteration is located in exon 1 (coding exon 1) of the DBX2 gene. This alteration results from a C to G substitution at nucleotide position 292, causing the proline (P) at amino acid position 98 to be replaced by an alanine (A). 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	0.064
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.70	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.76	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.44
Sift	Benign	0.058	T
Sift4G	Benign	0.083	T
Polyphen		1.0	D
Vest4		0.36
MutPred		0.56		Gain of catalytic residue at P98 (P = 0.0648);
MVP		0.58
MPC		0.15
ClinPred		0.74	D
GERP RS		2.4
Varity_R		0.10
gMVP		0.33

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: rs200605636; hg19: chr12-45444419;