NM_005315.2:c.263C>T

Variant names:

• chr22-19149913-G-A
• rs567016219
• NM_005315.2:c.263C>T

Variant summary

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

The NM_005315.2(GSC2):​c.263C>T​(p.Ala88Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000912 in 1,344,474 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A88S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (0 hom.)
• Consequence: GSC2 NM_005315.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.00
• Publications: 1 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=0.11873588).

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.263C>T	p.Ala88Val	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.263C>T	p.Ala88Val	missense	Exon 2 of 3	ENSP00000086933.2	O15499

Frequencies

GnomAD3 genomes AF: 0.000688 AC: 104 AN: 151236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000791

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000981

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000959

Gnomad OTH AF: 0.000963

GnomAD2 exomes AF: 0.000661 AC: 2 AN: 3024 AF XY: 0.000503

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00110

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000940 AC: 1122 AN: 1193130 Hom.: 0 Cov.: 32 AF XY: 0.000916 AC XY: 527 AN XY: 575434

African (AFR) AF: 0.000129 AC: 3 AN: 23292

American (AMR) AF: 0.00111 AC: 10 AN: 9042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16532

East Asian (EAS) AF: 0.00 AC: 0 AN: 26802

South Asian (SAS) AF: 0.00 AC: 0 AN: 49332

European-Finnish (FIN) AF: 0.0000680 AC: 2 AN: 29408

Middle Eastern (MID) AF: 0.000293 AC: 1 AN: 3418

European-Non Finnish (NFE) AF: 0.00109 AC: 1072 AN: 986274

Other (OTH) AF: 0.000693 AC: 34 AN: 49030

GnomAD4 genome AF: 0.000687 AC: 104 AN: 151344 Hom.: 0 Cov.: 33 AF XY: 0.000635 AC XY: 47 AN XY: 73996

African (AFR) AF: 0.000579 AC: 24 AN: 41422

American (AMR) AF: 0.000790 AC: 12 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

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

European-Finnish (FIN) AF: 0.0000981 AC: 1 AN: 10196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000959 AC: 65 AN: 67782

Other (OTH) AF: 0.000953 AC: 2 AN: 2098

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000756

ExAC AF: 0.000436 AC: 11

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	0.095
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.38	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.068
Sift	Benign	0.087	T
Sift4G	Benign	0.15	T
Polyphen		0.29	B
Vest4		0.17
MutPred		0.31		Gain of sheet (P = 0.0125)
MVP		0.36
MPC		0.43
ClinPred		0.043	T
GERP RS		1.6
PromoterAI		0.040	Neutral
Varity_R		0.048
gMVP		0.28
Mutation Taster		=89/11	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: rs567016219; hg19: chr22-19137426;