22-19039010-G-C

Variant names:

• chr22-19039010-G-C
• rs1171821139
• NM_005137.3:c.1508C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005137.3(DGCR2):​c.1508C>G​(p.Ser503Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DGCR2 NM_005137.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.69

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25615245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DGCR2	NM_005137.3	c.1508C>G	p.Ser503Cys	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.1508C>G	p.Ser503Cys	missense_variant	Exon 10 of 10	1	NM_005137.3	ENSP00000263196.7

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000813 AC: 2 AN: 246114 Hom.: 0 AF XY: 0.00000747 AC XY: 1 AN XY: 133804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460212 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726392

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1508C>G (p.S503C) alteration is located in exon 10 (coding exon 10) of the DGCR2 gene. This alteration results from a C to G substitution at nucleotide position 1508, causing the serine (S) at amino acid position 503 to be replaced by a cysteine (C). 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	-0.19	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.016	.;T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.97	.;.;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.97	N;.;N
REVEL	Benign	0.091
Sift	Benign	0.058	T;.;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.68	.;.;P
Vest4		0.12
MutPred		0.25		.;Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);
MVP		0.82
MPC		0.57
ClinPred		0.51	D
GERP RS		5.4
Varity_R		0.074
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: rs1171821139; hg19: chr22-19026523;