22-19041093-G-C

Variant names:

• chr22-19041093-G-C
• rs750187218
• NM_005137.3:c.1361C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005137.3(DGCR2):​c.1361C>G​(p.Ser454Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S454F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DGCR2 NM_005137.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.88
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005137.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGCR2	NM_005137.3	MANE Select	c.1361C>G	p.Ser454Cys	missense	Exon 9 of 10	NP_005128.1	P98153-1
	DGCR2	NM_001184781.2		c.1352C>G	p.Ser451Cys	missense	Exon 9 of 10	NP_001171710.1
	DGCR2	NM_001173533.2		c.1238C>G	p.Ser413Cys	missense	Exon 8 of 9	NP_001167004.1	P98153-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGCR2	ENST00000263196.12	TSL:1 MANE Select	c.1361C>G	p.Ser454Cys	missense	Exon 9 of 10	ENSP00000263196.7	P98153-1
	DGCR2	ENST00000389262.8	TSL:1	n.*932C>G		non_coding_transcript_exon	Exon 10 of 11	ENSP00000373914.5	Q5CZ70
	DGCR2	ENST00000389262.8	TSL:1	n.*932C>G		3_prime_UTR	Exon 10 of 11	ENSP00000373914.5	Q5CZ70

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248874 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 6.85e-7 AC: 1 AN: 1459520 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725874

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25948

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110510

Other (OTH) AF: 0.00 AC: 0 AN: 60330

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000245 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.065	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.4	L
PhyloP100		9.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.93	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.28		Loss of glycosylation at S454 (P = 0.0019)
MVP		0.98
MPC		0.80
ClinPred		0.66	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.57
Mutation Taster		=29/71	disease causing

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

Other links and lift over

dbSNP: rs750187218; hg19: chr22-19028606;