22-19039113-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The NM_005137.3(DGCR2):c.1405G>A(p.Ala469Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A469G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DGCR2 NM_005137.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.00

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05082804).
• BS2: High AC in GnomAdExome at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DGCR2	NM_005137.3	c.1405G>A	p.Ala469Thr	missense_variant	10/10	ENST00000263196.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DGCR2	ENST00000263196.12	c.1405G>A	p.Ala469Thr	missense_variant	10/10	1	NM_005137.3	P1
DGCR2	ENST00000389262.8	c.*976G>A		3_prime_UTR_variant, NMD_transcript_variant	11/11	1
DGCR2	ENST00000537045.5	c.1282G>A	p.Ala428Thr	missense_variant	9/9	2
DGCR2	ENST00000467659.1	n.1183G>A		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000323 AC: 8 AN: 247586 Hom.: 0 AF XY: 0.0000372 AC XY: 5 AN XY: 134486

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000436

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460716 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726666

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.0000330 AC: 4

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

Dec 04, 2023

The c.1405G>A (p.A469T) 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 1405, causing the alanine (A) at amino acid position 469 to be replaced by a threonine (T). 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	0.071
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.051	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.67	D;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.080	N;.;N
REVEL	Benign	0.093
Sift	Benign	0.18	T;.;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.0010	.;.;B
Vest4		0.073
MutPred		0.19		.;Gain of glycosylation at A469 (P = 0.0075);Gain of glycosylation at A469 (P = 0.0075);
MVP		0.66
MPC		0.26
ClinPred		0.034	T
GERP RS		3.4
Varity_R		0.043
gMVP		0.25

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: rs775001765; hg19: chr22-19026626;