12-45050720-C-T

Variant names:

• chr12-45050720-C-T
• rs771208101
• NM_001004329.3:c.208G>A

Variant summary

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

The NM_001004329.3(DBX2):​c.208G>A​(p.Gly70Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,339,406 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: DBX2 NM_001004329.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.622

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]

DBX2-AS1 (HGNC:55479): (DBX2 antisense RNA 1)

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=0.08283818).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DBX2	NM_001004329.3	c.208G>A	p.Gly70Ser	missense_variant	Exon 1 of 4	ENST00000332700.6	NP_001004329.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DBX2	ENST00000332700.6	c.208G>A	p.Gly70Ser	missense_variant	Exon 1 of 4	2	NM_001004329.3	ENSP00000331470.6
DBX2-AS1	ENST00000548424.1	n.-181C>T		upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1339406 Hom.: 0 Cov.: 33 AF XY: 0.00000152 AC XY: 1 AN XY: 659778

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: 0.0000140

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.47e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.0000126 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.208G>A (p.G70S) alteration is located in exon 1 (coding exon 1) of the DBX2 gene. This alteration results from a G to A substitution at nucleotide position 208, causing the glycine (G) at amino acid position 70 to be replaced by a serine (S). 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	0.079
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	3.2
DANN	Benign	0.87
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.14
Sift	Benign	0.21	T
Sift4G	Benign	0.84	T
Polyphen		0.0030	B
Vest4		0.095
MutPred		0.24		Gain of glycosylation at G70 (P = 0.0044);
MVP		0.25
MPC		0.15
ClinPred		0.075	T
GERP RS		-3.7
Varity_R		0.045
gMVP		0.29

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: rs771208101; hg19: chr12-45444503;