Genetic Variant DGCR2:p.Arg492His (chr22-19039043-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0023 ( 4 hom., cov: 34)

Exomes 𝑓: 0.0014 ( 28 hom. )

Consequence

DGCR2
NM_005137.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.633

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 2652852.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 357 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DGCR2	NM_005137.3 link	c.1475G>A	p.Arg492His	missense_variant	Exon 10 of 10	ENST00000263196.12	NP_005128.1	P98153-1Q8IWC8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DGCR2	ENST00000263196.12 link	c.1475G>A	p.Arg492His	missense_variant	Exon 10 of 10	1	NM_005137.3	ENSP00000263196.7		P98153-1

Frequencies

GnomAD3 genomes

AF:

0.00235

AC:

358

AN:

152218

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00297

AC:

734

AN:

247198

Hom.:

AF XY:

0.00276

AC XY:

371

AN XY:

134352

show subpopulations

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 SAS exome

AF:

0.000654

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.:

Cov.:

AF XY:

0.00135

AC XY:

984

AN XY:

726638

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00107

Gnomad4 EAS exome

AF:

0.00882

Gnomad4 SAS exome

AF:

0.000522

Gnomad4 FIN exome

AF:

0.0225

Gnomad4 NFE exome

AF:

0.000304

Gnomad4 OTH exome

AF:

0.00131

GnomAD4 genome

AF:

0.00234

AC:

357

AN:

152336

Hom.:

Cov.:

AF XY:

0.00361

AC XY:

269

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00598

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0250

Gnomad4 NFE

AF:

0.000706

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000691

Hom.:

Bravo

AF:

0.000393

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00255

AC:

310

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DGCR2: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.82

CADD

Benign

8.8

DANN

Benign

0.78

DEOGEN2

Benign

0.0047

.;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.84

T;T;T

MetaRNN

Benign

0.0036

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

.;.;N

PrimateAI

Benign

0.30

PROVEAN

Benign

0.050

N;.;N

REVEL

Benign

0.16

Sift

Benign

0.68

T;.;T

Sift4G

Benign

0.58

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.025

MVP

0.25

MPC

0.33

ClinPred

0.029

GERP RS

-7.4

Varity_R

0.013

gMVP

0.21

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over