15-52124617-G-T

Variant names:

• chr15-52124617-G-T
• rs749597091
• NM_016194.4:c.1032C>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_016194.4(GNB5):​c.1032C>A​(p.Tyr344*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GNB5 NM_016194.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 2.59
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• gnb5-related intellectual disability-cardiac arrhythmia syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000259709 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-52124617-G-T is Pathogenic according to our data. Variant chr15-52124617-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 450608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016194.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNB5	NM_016194.4	MANE Select	c.1032C>A	p.Tyr344*	stop_gained	Exon 12 of 13	NP_057278.2
	GNB5	NM_006578.4		c.906C>A	p.Tyr302*	stop_gained	Exon 10 of 11	NP_006569.1	O14775-2
	GNB5	NM_001379343.1		c.750C>A	p.Tyr250*	stop_gained	Exon 10 of 11	NP_001366272.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNB5	ENST00000261837.12	TSL:5 MANE Select	c.1032C>A	p.Tyr344*	stop_gained	Exon 12 of 13	ENSP00000261837.7	O14775-1
	GNB5	ENST00000358784.11	TSL:1	c.906C>A	p.Tyr302*	stop_gained	Exon 10 of 11	ENSP00000351635.7	O14775-2
	GNB5	ENST00000396335.8	TSL:1	c.696C>A	p.Tyr232*	stop_gained	Exon 8 of 9	ENSP00000379626.4	O14775-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251104 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461628 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727110

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111864

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Gnb5-related intellectual disability-cardiac arrhythmia syndrome (3)
1	-	-	Language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.6
Vest4		0.92
GERP RS		4.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs749597091; hg19: chr15-52416814;