Genetic Variant SHISA8:p.Gly232Glu (chr22-41910524-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001207020.3(SHISA8):c.695G>A(p.Gly232Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000965 in 1,244,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000092 ( 0 hom. )

Consequence

SHISA8
NM_001207020.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.755

Variant links:

Genes affected

SHISA8 (HGNC:18351): (shisa family member 8) Predicted to be involved in regulation of AMPA receptor activity and regulation of short-term neuronal synaptic plasticity. Predicted to be integral component of membrane. Predicted to be part of AMPA glutamate receptor complex. Predicted to be active in dendritic spine membrane; postsynaptic density; and postsynaptic membrane. [provided by Alliance of Genome Resources, Apr 2022]

SHISA8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20771748).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SHISA8	NM_001207020.3 link	c.695G>A	p.Gly232Glu	missense_variant	Exon 3 of 4	ENST00000621082.2	NP_001193949.1
SHISA8	NM_001353438.2 link	c.980G>A	p.Gly327Glu	missense_variant	Exon 3 of 4		NP_001340367.1
SHISA8	NM_001353439.2 link	c.872G>A	p.Gly291Glu	missense_variant	Exon 3 of 4		NP_001340368.1
SHISA8	XM_006724256.5 link	c.860G>A	p.Gly287Glu	missense_variant	Exon 3 of 4		XP_006724319.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHISA8	ENST00000621082.2 link	c.695G>A	p.Gly232Glu	missense_variant	Exon 3 of 4	5	NM_001207020.3	ENSP00000481203.1		B8ZZ34-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151872

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000388

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000916

AC:

AN:

1092214

Hom.:

Cov.:

AF XY:

0.00000769

AC XY:

AN XY:

520320

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000115

Gnomad4 SAS exome

AF:

0.0000872

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000108

Gnomad4 OTH exome

AF:

0.0000916

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151872

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74192

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

Asia WGS

AF:

0.000578

AC:

AN:

3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.695G>A (p.G232E) alteration is located in exon 3 (coding exon 3) of the SHISA8 gene. This alteration results from a G to A substitution at nucleotide position 695, causing the glycine (G) at amino acid position 232 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.91

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.51

MetaRNN

Benign

0.21

PrimateAI

Uncertain

0.61

Sift4G

Uncertain

0.057

Vest4

0.28

MVP

0.37

GERP RS

1.8

Varity_R

0.050

gMVP

0.32

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over