22-19038963-C-T

Variant names:

• chr22-19038963-C-T
• rs138506410
• NM_005137.3:c.1555G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005137.3(DGCR2):​c.1555G>A​(p.Val519Met) variant causes a missense change. The variant allele was found at a frequency of 0.000111 in 1,611,686 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: DGCR2 NM_005137.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.97

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.126865).
• BS2: High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DGCR2	NM_005137.3	c.1555G>A	p.Val519Met	missense_variant	Exon 10 of 10	ENST00000263196.12	NP_005128.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DGCR2	ENST00000263196.12	c.1555G>A	p.Val519Met	missense_variant	Exon 10 of 10	1	NM_005137.3	ENSP00000263196.7

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152220 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000212 AC: 52 AN: 245110 Hom.: 0 AF XY: 0.000203 AC XY: 27 AN XY: 133264

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000234

Gnomad NFE exome AF: 0.000356

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.000104 AC: 152 AN: 1459466 Hom.: 1 Cov.: 30 AF XY: 0.000109 AC XY: 79 AN XY: 726012

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000287

Gnomad4 NFE exome AF: 0.0000999

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152220 Hom.: 0 Cov.: 34 AF XY: 0.000134 AC XY: 10 AN XY: 74370

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000271 Hom.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000313 AC: 38

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1555G>A (p.V519M) alteration is located in exon 10 (coding exon 10) of the DGCR2 gene. This alteration results from a G to A substitution at nucleotide position 1555, causing the valine (V) at amino acid position 519 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	.;T;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.0	.;.;L
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.18	N;.;N
REVEL	Benign	0.13
Sift	Benign	0.066	T;.;T
Sift4G	Uncertain	0.039	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.22
MVP		0.70
MPC		0.28
ClinPred		0.070	T
GERP RS		4.4
Varity_R		0.032
gMVP		0.42

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: rs138506410; hg19: chr22-19026476;