22-19039047-G-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.1471C>T(p.Arg491Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000789 in 1,613,022 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.00041 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00083 (1 hom.)
• Consequence: DGCR2 NM_005137.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.48

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=0.15576902).
• BS2: High AC in GnomAd at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DGCR2	NM_005137.3	c.1471C>T	p.Arg491Trp	missense_variant	10/10	ENST00000263196.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DGCR2	ENST00000263196.12	c.1471C>T	p.Arg491Trp	missense_variant	10/10	1	NM_005137.3	P1
DGCR2	ENST00000389262.8	c.*1042C>T		3_prime_UTR_variant, NMD_transcript_variant	11/11	1
DGCR2	ENST00000537045.5	c.1348C>T	p.Arg450Trp	missense_variant	9/9	2
DGCR2	ENST00000467659.1	n.1249C>T		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152234 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000250 AC: 62 AN: 247540 Hom.: 0 AF XY: 0.000283 AC XY: 38 AN XY: 134442

Gnomad AFR exome AF: 0.000249

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000390

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000829 AC: 1211 AN: 1460788 Hom.: 1 Cov.: 30 AF XY: 0.000819 AC XY: 595 AN XY: 726700

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00101

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152234 Hom.: 0 Cov.: 34 AF XY: 0.000336 AC XY: 25 AN XY: 74370

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000681 Hom.: 0

Bravo AF: 0.000419

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.00125

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2021

The c.1471C>T (p.R491W) alteration is located in exon 10 (coding exon 10) of the DGCR2 gene. This alteration results from a C to T substitution at nucleotide position 1471, causing the arginine (R) at amino acid position 491 to be replaced by a tryptophan (W). 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	0.088
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.16
Eigen_PC	Benign	0.080
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.6	N;.;N
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.018	D;D;D
Polyphen		0.98	.;.;D
Vest4		0.19
MVP		0.82
MPC		0.60
ClinPred		0.076	T
GERP RS		4.3
Varity_R		0.051
gMVP		0.30

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: rs139200875; hg19: chr22-19026560;