NM_005137.3:c.1555G>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005137.3(DGCR2):​c.1555G>T​(p.Val519Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V519M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DGCR2 NM_005137.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.97
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24457914).

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.1555G>T	p.Val519Leu	missense	Exon 10 of 10	NP_005128.1	P98153-1
	DGCR2	NM_001184781.2		c.1546G>T	p.Val516Leu	missense	Exon 10 of 10	NP_001171710.1
	DGCR2	NM_001173533.2		c.1432G>T	p.Val478Leu	missense	Exon 9 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.1555G>T	p.Val519Leu	missense	Exon 10 of 10	ENSP00000263196.7	P98153-1
	DGCR2	ENST00000389262.8	TSL:1	n.*1126G>T		non_coding_transcript_exon	Exon 11 of 11	ENSP00000373914.5	Q5CZ70
	DGCR2	ENST00000389262.8	TSL:1	n.*1126G>T		3_prime_UTR	Exon 11 of 11	ENSP00000373914.5	Q5CZ70

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459466 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726012

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111392

Other (OTH) AF: 0.00 AC: 0 AN: 60308

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.060
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.0	L
PhyloP100		4.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.15
Sift	Uncertain	0.017	D
Sift4G	Benign	0.084	T
Polyphen		1.0	D
Vest4		0.33
MutPred		0.16		Loss of sheet (P = 0.0457)
MVP		0.68
MPC		0.28
ClinPred		0.25	T
GERP RS		4.4
Varity_R		0.050
gMVP		0.39
Mutation Taster		=88/12	polymorphism

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: rs138506410; hg19: chr22-19026476;