22-19149095-C-T

Variant names:

• chr22-19149095-C-T
• rs1183084024
• NM_005315.2:c.514G>A

Variant summary

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

The NM_005315.2(GSC2):​c.514G>A​(p.Val172Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. 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. V172F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GSC2 NM_005315.2 missense, splice_region
• Scores: Splicing: ADA: 0.9956
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.50
• Publications: 0 publications found

Genes affected

GSC2 (HGNC:4613): (goosecoid homeobox 2) Goosecoidlike (GSCL), a homeodomain-containing gene, resides in the critical region for VCFS/DGS on 22q11. Velocardiofacial syndrome (VCFS) is a developmental disorder characterized by conotruncal heart defects, craniofacial anomalies, and learning disabilities. VCFS is phenotypically related to DiGeorge syndrome (DGS) and both syndromes are associated with hemizygous 22q11 deletions. Because many of the tissues and structures affected in VCFS/DGS derive from the pharyngeal arches of the developing embryo, it is believed that haploinsufficiency of a gene involved in embryonic development may be responsible for its etiology. The gene is expressed in a limited number of adult tissues, as well as in early human development. [provided by RefSeq, Jul 2008]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005315.2. 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
	GSC2	NM_005315.2	MANE Select	c.514G>A	p.Val172Ile	missense splice_region	Exon 3 of 3	NP_005306.1	O15499

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSC2	ENST00000086933.3	TSL:5 MANE Select	c.514G>A	p.Val172Ile	missense splice_region	Exon 3 of 3	ENSP00000086933.2	O15499

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.76	N
PhyloP100		5.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.0	N
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.72		Loss of disorder (P = 0.1326)
MVP		0.70
MPC		1.2
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.54
gMVP		0.52
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		0.11		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: rs1183084024; hg19: chr22-19136608;