1-1846651-T-G

Variant names:

• chr1-1846651-T-G
• rs12126768
• NM_002074.5:c.-95-7413A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002074.5(GNB1):​c.-95-7413A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 152,114 control chromosomes in the GnomAD database, including 1,901 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (1901 hom., cov: 31)
• Consequence: GNB1 NM_002074.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.293
• Publications: 7 publications found

Genes affected

GNB1 (HGNC:4396): (G protein subunit beta 1) 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

GNB1 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 42

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNB1	NM_002074.5	c.-95-7413A>C		intron_variant	Intron 1 of 11	ENST00000378609.9	NP_002065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNB1	ENST00000378609.9	c.-95-7413A>C		intron_variant	Intron 1 of 11	1	NM_002074.5	ENSP00000367872.3

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22813 AN: 151996 Hom.: 1906 Cov.: 31

Gnomad AFR AF: 0.0908

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.169

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.150 AC: 22809 AN: 152114 Hom.: 1901 Cov.: 31 AF XY: 0.151 AC XY: 11265 AN XY: 74374

African (AFR) AF: 0.0907 AC: 3769 AN: 41536

American (AMR) AF: 0.133 AC: 2029 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 929 AN: 3466

East Asian (EAS) AF: 0.209 AC: 1083 AN: 5176

South Asian (SAS) AF: 0.209 AC: 1006 AN: 4814

European-Finnish (FIN) AF: 0.159 AC: 1678 AN: 10586

Middle Eastern (MID) AF: 0.305 AC: 89 AN: 292

European-Non Finnish (NFE) AF: 0.173 AC: 11735 AN: 67962

Other (OTH) AF: 0.167 AC: 351 AN: 2100

Alfa AF: 0.133 Hom.: 537

Bravo AF: 0.147

Asia WGS AF: 0.165 AC: 576 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.5
DANN	Benign	0.50
PhyloP100		0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12126768; hg19: chr1-1778090;