Variant 22-41910096-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001207020.3(SHISA8):c.863C>G(p.Pro288Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00561 in 1,239,556 control chromosomes in the GnomAD database, including 24 homozygotes. 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 0.0039 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0058 ( 20 hom. )

Consequence

SHISA8
NM_001207020.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0950

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010100037).

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SHISA8	NM_001207020.3 linkuse as main transcript	c.863C>G	p.Pro288Arg	missense_variant	4/4	ENST00000621082.2
SHISA8	NM_001353438.2 linkuse as main transcript	c.1148C>G	p.Pro383Arg	missense_variant	4/4
SHISA8	NM_001353439.2 linkuse as main transcript	c.1040C>G	p.Pro347Arg	missense_variant	4/4
SHISA8	XM_006724256.5 linkuse as main transcript	c.1028C>G	p.Pro343Arg	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHISA8	ENST00000621082.2 linkuse as main transcript	c.863C>G	p.Pro288Arg	missense_variant	4/4	5	NM_001207020.3	P1	B8ZZ34-1

Frequencies

GnomAD3 genomes

AF:

0.00392

AC:

595

AN:

151914

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00512

Gnomad ASJ

AF:

0.0132

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000569

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00587

Gnomad OTH

AF:

0.00478

GnomAD4 exome

AF:

0.00584

AC:

6355

AN:

1087534

Hom.:

Cov.:

AF XY:

0.00585

AC XY:

3011

AN XY:

514346

show subpopulations

Gnomad4 AFR exome

AF:

0.000837

Gnomad4 AMR exome

AF:

0.00304

Gnomad4 ASJ exome

AF:

0.0163

Gnomad4 EAS exome

AF:

0.0000383

Gnomad4 SAS exome

AF:

0.000526

Gnomad4 FIN exome

AF:

0.00130

Gnomad4 NFE exome

AF:

0.00625

Gnomad4 OTH exome

AF:

0.00555

GnomAD4 genome

AF:

0.00391

AC:

595

AN:

152022

Hom.:

Cov.:

AF XY:

0.00361

AC XY:

268

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00511

Gnomad4 ASJ

AF:

0.0132

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000569

Gnomad4 NFE

AF:

0.00587

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00339

Hom.:

Bravo

AF:

0.00403

Asia WGS

AF:

0.000588

AC:

AN:

3418

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 29, 2023

The c.863C>G (p.P288R) alteration is located in exon 4 (coding exon 4) of the SHISA8 gene. This alteration results from a C to G substitution at nucleotide position 863, causing the proline (P) at amino acid position 288 to be replaced by an arginine (R). 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

0.081

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.48

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.37

MetaRNN

Benign

0.010

PrimateAI

Pathogenic

0.82

Sift4G

Benign

0.30

Vest4

0.29

MVP

0.40

GERP RS

2.9

Varity_R

0.025

gMVP

0.39

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