22-19150115-C-T

Variant names:

• chr22-19150115-C-T
• rs1267929071
• NM_005315.2:c.169G>A

Variant summary

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

The NM_005315.2(GSC2):​c.169G>A​(p.Gly57Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000272 in 147,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GSC2 NM_005315.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.706

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

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=0.16868985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSC2	NM_005315.2	c.169G>A	p.Gly57Arg	missense_variant	Exon 1 of 3	ENST00000086933.3	NP_005306.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSC2	ENST00000086933.3	c.169G>A	p.Gly57Arg	missense_variant	Exon 1 of 3	5	NM_005315.2	ENSP00000086933.2

Frequencies

GnomAD3 genomes AF: 0.0000272 AC: 4 AN: 147058 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000605

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000355 AC: 30 AN: 846250 Hom.: 0 Cov.: 16 AF XY: 0.0000304 AC XY: 12 AN XY: 394296

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000392

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000272 AC: 4 AN: 147058 Hom.: 0 Cov.: 33 AF XY: 0.0000419 AC XY: 3 AN XY: 71560

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000605

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Benign	0.069	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.43	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.90	L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.087
Sift	Benign	0.36	T
Sift4G	Benign	0.49	T
Polyphen		0.029	B
Vest4		0.17
MutPred		0.36		Gain of solvent accessibility (P = 0.0037);
MVP		0.25
MPC		0.72
ClinPred		0.11	T
GERP RS		1.5
Varity_R		0.055
gMVP		0.34

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: rs1267929071; hg19: chr22-19137628;