22-19150115-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 15/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G57W) has been classified as Uncertain significance.

• 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
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16868985).

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.169G>A	p.Gly57Arg	missense	Exon 1 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.169G>A	p.Gly57Arg	missense	Exon 1 of 3	ENSP00000086933.2	O15499

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

African (AFR) AF: 0.00 AC: 0 AN: 16004

American (AMR) AF: 0.00 AC: 0 AN: 1866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5778

East Asian (EAS) AF: 0.00 AC: 0 AN: 5630

South Asian (SAS) AF: 0.00 AC: 0 AN: 17266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1728

European-Non Finnish (NFE) AF: 0.0000392 AC: 30 AN: 765850

Other (OTH) AF: 0.00 AC: 0 AN: 28470

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

African (AFR) AF: 0.00 AC: 0 AN: 40932

American (AMR) AF: 0.00 AC: 0 AN: 14836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8638

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000605 AC: 4 AN: 66070

Other (OTH) AF: 0.00 AC: 0 AN: 2028

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.71
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
PromoterAI		-0.011	Neutral
Varity_R		0.055
gMVP		0.34
Mutation Taster		=89/11	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: rs1267929071; hg19: chr22-19137628;