22-19039043-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 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 GnomAd at 358 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DGCR2	NM_005137.3	c.1475G>A	p.Arg492His	missense_variant	10/10	ENST00000263196.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DGCR2	ENST00000263196.12	c.1475G>A	p.Arg492His	missense_variant	10/10	1	NM_005137.3	P1
DGCR2	ENST00000389262.8	c.*1046G>A		3_prime_UTR_variant, NMD_transcript_variant	11/11	1
DGCR2	ENST00000537045.5	c.1352G>A	p.Arg451His	missense_variant	9/9	2
DGCR2	ENST00000467659.1	n.1253G>A		non_coding_transcript_exon_variant	4/4	5

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

GnomAD3 exomes AF: 0.00297 AC: 734 AN: 247198 Hom.: 8 AF XY: 0.00276 AC XY: 371 AN XY: 134352

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.: 28 Cov.: 30 AF XY: 0.00135 AC XY: 984 AN XY: 726638

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.: 4 Cov.: 34 AF XY: 0.00361 AC XY: 269 AN XY: 74484

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.: 0

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

DGCR2: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.84	T;T;T
MetaRNN	Benign	0.0036	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
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	T
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

Other links and lift over

dbSNP: rs141421532; hg19: chr22-19026556; COSMIC: COSV54218290; COSMIC: COSV54218290;