chr22-19041084-G-T

Variant names:

• chr22-19041084-G-T
• rs752930174
• NM_005137.3:c.1370C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005137.3(DGCR2):​c.1370C>A​(p.Pro457Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,206 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P457L) 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: 8.01
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1370C>A	p.Pro457Gln	missense	Exon 9 of 10	NP_005128.1	P98153-1
	DGCR2	NM_001184781.2		c.1361C>A	p.Pro454Gln	missense	Exon 9 of 10	NP_001171710.1
	DGCR2	NM_001173533.2		c.1247C>A	p.Pro416Gln	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.1370C>A	p.Pro457Gln	missense	Exon 9 of 10	ENSP00000263196.7	P98153-1
	DGCR2	ENST00000389262.8	TSL:1	n.*941C>A		non_coding_transcript_exon	Exon 10 of 11	ENSP00000373914.5	Q5CZ70
	DGCR2	ENST00000389262.8	TSL:1	n.*941C>A		3_prime_UTR	Exon 10 of 11	ENSP00000373914.5	Q5CZ70

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458206 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725072

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25830

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 85782

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109836

Other (OTH) AF: 0.00 AC: 0 AN: 60272

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.5	L
PhyloP100		8.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.039	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.23		Gain of sheet (P = 0.0477)
MVP		0.99
MPC		0.27
ClinPred		0.82	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.16
gMVP		0.54
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs752930174; hg19: chr22-19028597;