chr22-19039046-C-T

Variant names:

• chr22-19039046-C-T
• rs150816482
• NM_005137.3:c.1472G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005137.3(DGCR2):​c.1472G>A​(p.Arg491Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,612,962 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. R491P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: DGCR2 NM_005137.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.117
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044599473).
• BS2: High AC in GnomAd4 at 20 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005137.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGCR2	NM_005137.3	MANE Select	c.1472G>A	p.Arg491Gln	missense	Exon 10 of 10	NP_005128.1	P98153-1
	DGCR2	NM_001184781.2		c.1463G>A	p.Arg488Gln	missense	Exon 10 of 10	NP_001171710.1
	DGCR2	NM_001173533.2		c.1349G>A	p.Arg450Gln	missense	Exon 9 of 9	NP_001167004.1	P98153-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGCR2	ENST00000263196.12	TSL:1 MANE Select	c.1472G>A	p.Arg491Gln	missense	Exon 10 of 10	ENSP00000263196.7	P98153-1
	DGCR2	ENST00000389262.8	TSL:1	n.*1043G>A		non_coding_transcript_exon	Exon 11 of 11	ENSP00000373914.5	Q5CZ70
	DGCR2	ENST00000389262.8	TSL:1	n.*1043G>A		3_prime_UTR	Exon 11 of 11	ENSP00000373914.5	Q5CZ70

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152214 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000190 AC: 47 AN: 247466 AF XY: 0.000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00430

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000907

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000108 AC: 158 AN: 1460748 Hom.: 1 Cov.: 30 AF XY: 0.000105 AC XY: 76 AN XY: 726682

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00402 AC: 105 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111924

Other (OTH) AF: 0.000298 AC: 18 AN: 60376

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152214 Hom.: 0 Cov.: 34 AF XY: 0.000161 AC XY: 12 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000651 Hom.: 1

Bravo AF: 0.000140

ExAC AF: 0.000140 AC: 17

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N
PhyloP100		-0.12
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.060
Sift	Benign	0.23	T
Sift4G	Benign	0.63	T
Polyphen		0.0010	B
Vest4		0.063
MutPred		0.17		Gain of relative solvent accessibility (P = 0.2363)
MVP		0.49
MPC		0.31
ClinPred		0.022	T
GERP RS		0.52
Varity_R		0.052
gMVP		0.21
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs150816482; hg19: chr22-19026559;