Genetic Variant GNB5:p.Ser123Trp (chr15-52153947-G-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_ModeratePP5_Moderate

The NM_016194.4(GNB5):c.368C>G(p.Ser123Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S123L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GNB5
NM_016194.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 9.82

Variant links:

Genes affected

GNB5 (HGNC:4401): (G protein subunit beta 5) Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. Alternatively spliced transcript variants encoding different isoforms exist. [provided by RefSeq, Jul 2008]

GNB5 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-52153947-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.902

PP5

Variant 15-52153947-G-C is Pathogenic according to our data. Variant chr15-52153947-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 977622.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-52153947-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GNB5	NM_016194.4 link	c.368C>G	p.Ser123Trp	missense_variant	Exon 4 of 13	ENST00000261837.12	NP_057278.2
GNB5	NM_006578.4 link	c.242C>G	p.Ser81Trp	missense_variant	Exon 2 of 11		NP_006569.1
GNB5	NM_001379343.1 link	c.86C>G	p.Ser29Trp	missense_variant	Exon 2 of 11		NP_001366272.1
GNB5	XM_011521162.4 link	c.242C>G	p.Ser81Trp	missense_variant	Exon 2 of 11		XP_011519464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNB5	ENST00000261837.12 link	c.368C>G	p.Ser123Trp	missense_variant	Exon 4 of 13	5	NM_016194.4	ENSP00000261837.7		O14775-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459082

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725756

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Global developmental delay

Pathogenic:1

Nov 01, 2019

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

homozygous -

Gnb5-related intellectual disability-cardiac arrhythmia syndrome

Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

D;.;.;T

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Uncertain

0.13

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.3

D;D;D;D

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;.;D

Vest4

0.82

MutPred

0.72

Loss of disorder (P = 0.0019);.;.;.;

MVP

0.92

MPC

1.4

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.80

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over