Genetic Variant NM_005315.2:c.215C>A (chr22-19150069-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005315.2(GSC2):c.215C>A(p.Pro72His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 852,760 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P72R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

GSC2
NM_005315.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.97

Publications

0 publications found

Variant links:

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]

GSC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25615197).

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>A	p.Pro72His	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>A	p.Pro72His	missense	Exon 1 of 3	ENSP00000086933.2	O15499

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000117

AC:

AN:

852760

Hom.:

Cov.:

AF XY:

0.00000758

AC XY:

AN XY:

395914

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

16120

American (AMR)

AF:

0.00

AC:

AN:

1642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5550

East Asian (EAS)

AF:

0.00

AC:

AN:

4528

South Asian (SAS)

AF:

0.00

AC:

AN:

17422

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1694

European-Non Finnish (NFE)

AF:

0.0000129

AC:

AN:

774866

Other (OTH)

AF:

0.00

AC:

AN:

28432

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.062

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.29

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.30

MutationAssessor

Benign

0.90

PhyloP100

3.0

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.67

REVEL

Benign

0.13

Sift

Benign

0.032

Sift4G

Uncertain

0.012

Polyphen

0.012

Vest4

0.16

MutPred

0.29

Gain of catalytic residue at P72 (P = 0.0097)

MVP

0.27

MPC

0.71

ClinPred

0.25

GERP RS

2.6

PromoterAI

0.028

Neutral

(source)

Varity_R

0.22

gMVP

0.30

Mutation Taster

=93/7

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over