22-19150031-C-T

Variant names:

• chr22-19150031-C-T
• rs1299124524
• NM_005315.2:c.253G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_005315.2(GSC2):​c.253G>A​(p.Gly85Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,021,572 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 0.000034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: GSC2 NM_005315.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.602
• 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3925631).

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.253G>A	p.Gly85Arg	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.253G>A	p.Gly85Arg	missense	Exon 1 of 3	ENSP00000086933.2	O15499

Frequencies

GnomAD3 genomes AF: 0.0000341 AC: 5 AN: 146802 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: 0.000590

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000686 AC: 6 AN: 874662 Hom.: 0 Cov.: 30 AF XY: 0.00000491 AC XY: 2 AN XY: 407562

African (AFR) AF: 0.00 AC: 0 AN: 16716

American (AMR) AF: 0.00 AC: 0 AN: 2294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6224

East Asian (EAS) AF: 0.00 AC: 0 AN: 5718

South Asian (SAS) AF: 0.00 AC: 0 AN: 17592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1776

European-Non Finnish (NFE) AF: 0.00000760 AC: 6 AN: 789676

Other (OTH) AF: 0.00 AC: 0 AN: 29758

GnomAD4 genome AF: 0.0000340 AC: 5 AN: 146910 Hom.: 0 Cov.: 33 AF XY: 0.0000140 AC XY: 1 AN XY: 71550

African (AFR) AF: 0.00 AC: 0 AN: 41012

American (AMR) AF: 0.00 AC: 0 AN: 14798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.000591 AC: 3 AN: 5072

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65992

Other (OTH) AF: 0.00 AC: 0 AN: 2046

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

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	0.16
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	-0.098	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.60
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.20
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.39	T
Polyphen		1.0	D
Vest4		0.063
MutPred		0.36		Gain of MoRF binding (P = 0.0059)
MVP		0.59
MPC		1.4
ClinPred		0.40	T
GERP RS		2.1
PromoterAI		-0.018	Neutral
Varity_R		0.17
gMVP		0.38
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: rs1299124524; hg19: chr22-19137544;