22-19150115-C-G

Variant names:

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

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>C​(p.Gly57Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000236 in 846,250 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• 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=0.169175).

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>C	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>C	p.Gly57Arg	missense	Exon 1 of 3	ENSP00000086933.2	O15499

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000236 AC: 2 AN: 846250 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 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: 0.00000131 AC: 1 AN: 765850

Other (OTH) AF: 0.0000351 AC: 1 AN: 28470

GnomAD4 genome Cov.: 33

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	0.94
DEOGEN2	Benign	0.069	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.43	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.71
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.10
Sift	Benign	0.36	T
Sift4G	Benign	0.49	T
Polyphen		0.013	B
Vest4		0.17
MutPred		0.36		Gain of solvent accessibility (P = 0.0037)
MVP		0.25
MPC		0.72
ClinPred		0.096	T
GERP RS		1.5
PromoterAI		0.0014	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;