22-19150052-C-T

Variant names:

• chr22-19150052-C-T
• rs1473693170
• NM_005315.2:c.232G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005315.2(GSC2):​c.232G>A​(p.Gly78Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000032 in 1,001,316 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: GSC2 NM_005315.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.31
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08846447).

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.232G>A	p.Gly78Arg	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.232G>A	p.Gly78Arg	missense	Exon 1 of 3	ENSP00000086933.2	O15499

Frequencies

GnomAD3 genomes AF: 0.000157 AC: 23 AN: 146762 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000135

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000105 AC: 9 AN: 854554 Hom.: 0 Cov.: 30 AF XY: 0.0000126 AC XY: 5 AN XY: 396874

African (AFR) AF: 0.000495 AC: 8 AN: 16150

American (AMR) AF: 0.00 AC: 0 AN: 1702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5598

East Asian (EAS) AF: 0.00 AC: 0 AN: 4480

South Asian (SAS) AF: 0.00 AC: 0 AN: 17420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1702

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 776230

Other (OTH) AF: 0.0000350 AC: 1 AN: 28592

GnomAD4 genome AF: 0.000157 AC: 23 AN: 146762 Hom.: 0 Cov.: 33 AF XY: 0.000154 AC XY: 11 AN XY: 71408

African (AFR) AF: 0.000514 AC: 21 AN: 40876

American (AMR) AF: 0.000135 AC: 2 AN: 14786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 5096

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8574

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65970

Other (OTH) AF: 0.00 AC: 0 AN: 2020

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000212

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.32
DANN	Benign	0.88
DEOGEN2	Benign	0.050	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.3
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.16
Sift	Benign	0.39	T
Sift4G	Benign	0.61	T
Polyphen		0.0010	B
Vest4		0.060
MutPred		0.30		Loss of catalytic residue at G78 (P = 0.0249)
MVP		0.12
MPC		0.51
ClinPred		0.057	T
GERP RS		-6.0
PromoterAI		0.012	Neutral
Varity_R		0.053
gMVP		0.28
Mutation Taster		=96/4	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: rs1473693170; hg19: chr22-19137565;