chr22-19150115-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005315.2(GSC2):​c.169G>T​(p.Gly57Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000906 in 993,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: GSC2 NM_005315.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38060784).

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>T	p.Gly57Trp	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>T	p.Gly57Trp	missense	Exon 1 of 3	ENSP00000086933.2	O15499

Frequencies

GnomAD3 genomes AF: 0.0000544 AC: 8 AN: 147058 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000195

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000118 AC: 1 AN: 846250 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 394296

African (AFR) AF: 0.0000625 AC: 1 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: 0.00 AC: 0 AN: 765850

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

GnomAD4 genome AF: 0.0000544 AC: 8 AN: 147058 Hom.: 0 Cov.: 33 AF XY: 0.0000559 AC XY: 4 AN XY: 71560

African (AFR) AF: 0.000195 AC: 8 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: 0.00 AC: 0 AN: 66070

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000718

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	0.13
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	-0.095	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.71
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.24
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.090	T
Polyphen		0.99	D
Vest4		0.28
MutPred		0.39		Gain of solvent accessibility (P = 0.0062)
MVP		0.64
MPC		1.2
ClinPred		0.64	D
GERP RS		1.5
PromoterAI		-0.0058	Neutral
Varity_R		0.078
gMVP		0.32
Mutation Taster		=86/14	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;