15-52124617-G-C

Position:

• chr15-52124617-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_016194.4(GNB5):​c.1032C>G​(p.Tyr344Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,628 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: GNB5 NM_016194.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 2.59

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.131 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-52124617-G-C is Pathogenic according to our data. Variant chr15-52124617-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 268102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-52124617-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNB5	NM_016194.4	c.1032C>G	p.Tyr344Ter	stop_gained	12/13	ENST00000261837.12	NP_057278.2
GNB5	NM_006578.4	c.906C>G	p.Tyr302Ter	stop_gained	10/11		NP_006569.1
GNB5	NM_001379343.1	c.750C>G	p.Tyr250Ter	stop_gained	10/11		NP_001366272.1
GNB5	XM_011521162.4	c.906C>G	p.Tyr302Ter	stop_gained	10/11		XP_011519464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNB5	ENST00000261837.12	c.1032C>G	p.Tyr344Ter	stop_gained	12/13	5	NM_016194.4	ENSP00000261837	P3
	ENST00000557898.1	n.57G>C		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251104 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135694

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461628 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 727110

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: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32280589, 31631344, 31720979, 32477400, 28327206, 33172956, 32203251, 27523599) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 04, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 08, 2020	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in GNB5 are known to be pathogenic (PMID: 21766168, 27523599). This variant has been observed in individual(s) with GNB5-related conditions (PMID: 27523599). ClinVar contains an entry for this variant (Variation ID: 268102). This variant is present in population databases (rs749597091, ExAC 0.006%). This sequence change creates a premature translational stop signal (p.Tyr344*) in the GNB5 gene. It is expected to result in an absent or disrupted protein product. -

Gnb5-related intellectual disability-cardiac arrhythmia syndrome Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Recurrent variant reported in 6 families from India and Pakistan -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 09, 2016	- -
Pathogenic, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	This variant was identified as compound heterozygous in an individual with devleopmental delay, intellectual disability, hypotonia, retinal dystrophy, arrhythmia. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.92
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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

Other links and lift over

dbSNP: rs749597091; hg19: chr15-52416814;