22-19041067-C-T

Variant names:

• chr22-19041067-C-T
• rs139943214
• NM_005137.3:c.1387G>A

Variant summary

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

The NM_005137.3(DGCR2):​c.1387G>A​(p.Asp463Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: DGCR2 NM_005137.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.24

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 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=0.13621715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DGCR2	NM_005137.3	c.1387G>A	p.Asp463Asn	missense_variant	Exon 9 of 10	ENST00000263196.12	NP_005128.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DGCR2	ENST00000263196.12	c.1387G>A	p.Asp463Asn	missense_variant	Exon 9 of 10	1	NM_005137.3	ENSP00000263196.7

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000413 AC: 1 AN: 242002 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130354

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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 Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74476

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	.;T;T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	0.0	.;.;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.020	N;.;N
REVEL	Benign	0.27
Sift	Benign	0.084	T;.;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.51	.;.;P
Vest4		0.26
MutPred		0.18		.;Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.95
MPC		0.77
ClinPred		0.45	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.14
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139943214; hg19: chr22-19028580;