rs1804373189

Variant names:

• chr7-100677377-G-A
• rs1804373189
• NM_005273.4:c.229G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-100677377-G-A
• chr7-100677377-G-C
• chr7-100677377-G-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_005273.4(GNB2):​c.229G>A​(p.Gly77Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G77E) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GNB2 NM_005273.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.14
• Publications: 3 publications found

Genes affected

GNB2 (HGNC:4398): (G protein subunit beta 2) 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. This gene contains a trinucleotide (CCG) repeat length polymorphism in its 5' UTR. [provided by RefSeq, Jul 2008]

GNB2 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with hypotonia and dysmorphic facies

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 4

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

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-100677378-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3776371.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 8 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.214 (above the threshold of 3.09). Trascript score misZ: 3.0761 (below the threshold of 3.09). GenCC associations: The gene is linked to sick sinus syndrome 4, neurodevelopmental disorder with hypotonia and dysmorphic facies.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89
• PP5: Variant 7-100677377-G-A is Pathogenic according to our data. Variant chr7-100677377-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 977754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005273.4. 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
	GNB2	NM_005273.4	MANE Select	c.229G>A	p.Gly77Arg	missense	Exon 5 of 10	NP_005264.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNB2	ENST00000303210.9	TSL:1 MANE Select	c.229G>A	p.Gly77Arg	missense	Exon 5 of 10	ENSP00000305260.4	P62879-1
	GNB2	ENST00000393924.1	TSL:1	c.229G>A	p.Gly77Arg	missense	Exon 4 of 9	ENSP00000377501.1	P62879-1
	GNB2	ENST00000879679.1		c.229G>A	p.Gly77Arg	missense	Exon 5 of 10	ENSP00000549738.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461598 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727116

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53256

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111900

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

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Neurodevelopmental disorder with hypotonia and dysmorphic facies (2)
1	-	-	GNB2-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.80	N
PhyloP100		8.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.020	D
Polyphen		0.98	D
Vest4		0.96
MutPred		0.71		Gain of methylation at K78 (P = 0.05)
MVP		0.83
MPC		2.6
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.95
Mutation Taster		=37/63	disease causing

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: rs1804373189; hg19: chr7-100275000;