rs1351939545

Variant names:

• chr22-19150069-G-C
• rs1351939545
• NM_005315.2:c.215C>G

Your query was ambiguous. Multiple possible variants found:

• chr22-19150069-G-C
• chr22-19150069-G-A
• chr22-19150069-G-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.215C>G​(p.Pro72Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000027 in 999,514 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 0.000048 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: GSC2 NM_005315.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.97
• 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=0.35752022).

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.215C>G	p.Pro72Arg	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.215C>G	p.Pro72Arg	missense	Exon 1 of 3	ENSP00000086933.2	O15499

Frequencies

GnomAD3 genomes AF: 0.0000477 AC: 7 AN: 146754 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: 0.0000910

Gnomad OTH AF: 0.000496

GnomAD4 exome AF: 0.0000235 AC: 20 AN: 852760 Hom.: 0 Cov.: 30 AF XY: 0.0000278 AC XY: 11 AN XY: 395914

African (AFR) AF: 0.00 AC: 0 AN: 16120

American (AMR) AF: 0.00 AC: 0 AN: 1642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5550

East Asian (EAS) AF: 0.00 AC: 0 AN: 4528

South Asian (SAS) AF: 0.00 AC: 0 AN: 17422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2506

Middle Eastern (MID) AF: 0.000590 AC: 1 AN: 1694

European-Non Finnish (NFE) AF: 0.0000194 AC: 15 AN: 774866

Other (OTH) AF: 0.000141 AC: 4 AN: 28432

GnomAD4 genome AF: 0.0000477 AC: 7 AN: 146754 Hom.: 0 Cov.: 33 AF XY: 0.0000280 AC XY: 2 AN XY: 71368

African (AFR) AF: 0.00 AC: 0 AN: 40904

American (AMR) AF: 0.00 AC: 0 AN: 14790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000910 AC: 6 AN: 65952

Other (OTH) AF: 0.000496 AC: 1 AN: 2016

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000340

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	0.087
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.34	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.90	L
PhyloP100		3.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.18
Sift	Benign	0.047	D
Sift4G	Uncertain	0.042	D
Polyphen		0.72	P
Vest4		0.17
MutPred		0.26		Loss of catalytic residue at G71 (P = 0.191)
MVP		0.42
MPC		0.49
ClinPred		0.26	T
GERP RS		2.6
PromoterAI		0.048	Neutral
Varity_R		0.14
gMVP		0.22
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1351939545; hg19: chr22-19137582;