22-19039043-C-T

Variant names:

• chr22-19039043-C-T
• rs141421532
• NM_005137.3:c.1475G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005137.3(DGCR2):​c.1475G>A​(p.Arg492His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,612,962 control chromosomes in the GnomAD database, including 32 homozygotes. 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 Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R492C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (4 hom., cov: 34)
  • Exomes 𝑓: 0.0014 (28 hom.)
• Consequence: DGCR2 NM_005137.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.633
• Publications: 6 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036392808).
• BP6: Variant 22-19039043-C-T is Benign according to our data. Variant chr22-19039043-C-T is described in ClinVar as Benign. ClinVar VariationId is 2652852.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 357 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.1475G>A	p.Arg492His	missense	Exon 10 of 10	NP_005128.1	P98153-1
	DGCR2	NM_001184781.2		c.1466G>A	p.Arg489His	missense	Exon 10 of 10	NP_001171710.1
	DGCR2	NM_001173533.2		c.1352G>A	p.Arg451His	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.1475G>A	p.Arg492His	missense	Exon 10 of 10	ENSP00000263196.7	P98153-1
	DGCR2	ENST00000389262.8	TSL:1	n.*1046G>A		non_coding_transcript_exon	Exon 11 of 11	ENSP00000373914.5	Q5CZ70
	DGCR2	ENST00000389262.8	TSL:1	n.*1046G>A		3_prime_UTR	Exon 11 of 11	ENSP00000373914.5	Q5CZ70

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 358 AN: 152218 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00596

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00297 AC: 734 AN: 247198 AF XY: 0.00276

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00300

Gnomad FIN exome AF: 0.0239

Gnomad NFE exome AF: 0.000963

Gnomad OTH exome AF: 0.00313

GnomAD4 exome AF: 0.00139 AC: 2033 AN: 1460626 Hom.: 28 Cov.: 30 AF XY: 0.00135 AC XY: 984 AN XY: 726638

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.000224 AC: 10 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26114

East Asian (EAS) AF: 0.00882 AC: 350 AN: 39700

South Asian (SAS) AF: 0.000522 AC: 45 AN: 86246

European-Finnish (FIN) AF: 0.0225 AC: 1180 AN: 52436

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5728

European-Non Finnish (NFE) AF: 0.000304 AC: 338 AN: 1111858

Other (OTH) AF: 0.00131 AC: 79 AN: 60360

GnomAD4 genome AF: 0.00234 AC: 357 AN: 152336 Hom.: 4 Cov.: 34 AF XY: 0.00361 AC XY: 269 AN XY: 74484

African (AFR) AF: 0.0000241 AC: 1 AN: 41576

American (AMR) AF: 0.000196 AC: 3 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00598 AC: 31 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0250 AC: 265 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68028

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000967 Hom.: 1

Bravo AF: 0.000393

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00255 AC: 310

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.8
DANN	Benign	0.78
DEOGEN2	Benign	0.0047	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.63
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.16
Sift	Benign	0.68	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.025
MVP		0.25
MPC		0.33
ClinPred		0.029	T
GERP RS		-7.4
Varity_R		0.013
gMVP		0.21
Mutation Taster		=99/1	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: rs141421532; hg19: chr22-19026556; COSMIC: COSV54218290; COSMIC: COSV54218290;