chr15-52122769-C-A

Position:

• chr15-52122769-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_016194.4(GNB5):​c.1177-1G>T variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNB5 NM_016194.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNB5	NM_016194.4	c.1177-1G>T		splice_acceptor_variant, intron_variant		ENST00000261837.12	NP_057278.2
GNB5	NM_006578.4	c.1051-1G>T		splice_acceptor_variant, intron_variant			NP_006569.1
GNB5	NM_001379343.1	c.895-1G>T		splice_acceptor_variant, intron_variant			NP_001366272.1
GNB5	XM_011521162.4	c.1051-1G>T		splice_acceptor_variant, intron_variant			XP_011519464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNB5	ENST00000261837.12	c.1177-1G>T		splice_acceptor_variant, intron_variant		5	NM_016194.4	ENSP00000261837.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gnb5-related intellectual disability-cardiac arrhythmia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neurogenetics Team, Indira Gandhi Institute of Child Health

Oct 16, 2024

The variation identified c.1177-1G>T is a novel one, the variant is absent in population databases like gnomAD v2.1.1 (PM2). The variant identified is a null variant and is identified in a gene where loss of function a known mechanism of disease causation (PVS1). No functional studies were done. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.93	D
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.56		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-52414966;