22-19039070-C-T

Position:

• chr22-19039070-C-T

Variant summary

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

The NM_005137.3(DGCR2):​c.1448G>A​(p.Gly483Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DGCR2 NM_005137.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

Genes affected

DGCR2 (HGNC:2845): (DiGeorge syndrome critical region gene 2) Deletions of the 22q11.2 have been associated with a wide range of developmental defects (notably DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome and isolated conotruncal cardiac defects) classified under the acronym CATCH 22. The DGCR2 gene encodes a novel putative adhesion receptor protein, which could play a role in neural crest cells migration, a process which has been proposed to be altered in DiGeorge syndrome. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

DGCR2 (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=0.1594652).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DGCR2	NM_005137.3	c.1448G>A	p.Gly483Asp	missense_variant	10/10	ENST00000263196.12	NP_005128.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DGCR2	ENST00000263196.12	c.1448G>A	p.Gly483Asp	missense_variant	10/10	1	NM_005137.3	ENSP00000263196.7

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460934 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726782

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: 0.0000190

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

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

Oct 01, 2024

The c.1448G>A (p.G483D) alteration is located in exon 10 (coding exon 10) of the DGCR2 gene. This alteration results from a G to A substitution at nucleotide position 1448, causing the glycine (G) at amino acid position 483 to be replaced by an aspartic acid (D). 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	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.0080	.;T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	.;.;L
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.21	N;.;N
REVEL	Benign	0.15
Sift	Uncertain	0.0060	D;.;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.68	.;.;P
Vest4		0.24
MutPred		0.19		.;Loss of catalytic residue at G483 (P = 0.0028);Loss of catalytic residue at G483 (P = 0.0028);
MVP		0.72
MPC		0.45
ClinPred		0.28	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-19026583;