22-19149729-C-G

Variant names:

• chr22-19149729-C-G
• NM_005315.2:c.447G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005315.2(GSC2):​c.447G>C​(p.Gln149His) variant causes a missense change. The variant allele was found at a frequency of 0.000000694 in 1,440,344 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GSC2 NM_005315.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.64
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.447G>C	p.Gln149His	missense	Exon 2 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.447G>C	p.Gln149His	missense	Exon 2 of 3	ENSP00000086933.2	O15499

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440344 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 715968

African (AFR) AF: 0.00 AC: 0 AN: 31002

American (AMR) AF: 0.00 AC: 0 AN: 43048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25516

East Asian (EAS) AF: 0.00 AC: 0 AN: 37632

South Asian (SAS) AF: 0.00 AC: 0 AN: 83692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1103592

Other (OTH) AF: 0.00 AC: 0 AN: 59464

GnomAD4 genome Cov.: 33

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	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.034	D
MutationAssessor	Benign	-0.27	N
PhyloP100		4.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	1.6	N
REVEL	Uncertain	0.49
Sift	Benign	1.0	T
Sift4G	Benign	0.42	T
Polyphen		0.083	B
Vest4		0.48
MutPred		0.50		Gain of catalytic residue at Q149 (P = 0.0055)
MVP		0.52
MPC		0.53
ClinPred		0.94	D
GERP RS		4.5
Varity_R		0.26
gMVP		0.66
Mutation Taster		=19/81	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

hg19: chr22-19137242;