NM_005273.4:c.268-11C>G

Variant names:

• chr7-100677487-C-G
• rs78530908
• NM_005273.4:c.268-11C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005273.4(GNB2):​c.268-11C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.027 in 1,613,168 control chromosomes in the GnomAD database, including 728 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (52 hom., cov: 33)
  • Exomes 𝑓: 0.028 (676 hom.)
• Consequence: GNB2 NM_005273.4 intron
• Scores: Splicing: ADA: 0.0005857
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0790
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-100677487-C-G is Benign according to our data. Variant chr7-100677487-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1195386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0197 (3000/152362) while in subpopulation NFE AF = 0.0305 (2078/68032). AF 95% confidence interval is 0.0295. There are 52 homozygotes in GnomAd4. There are 1415 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3000 Unknown,AD gene.

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.268-11C>G		intron	N/A	NP_005264.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNB2	ENST00000303210.9	TSL:1 MANE Select	c.268-11C>G		intron	N/A	ENSP00000305260.4	P62879-1
	GNB2	ENST00000393924.1	TSL:1	c.268-11C>G		intron	N/A	ENSP00000377501.1	P62879-1
	GNB2	ENST00000879679.1		c.268-11C>G		intron	N/A	ENSP00000549738.1

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 3001 AN: 152244 Hom.: 52 Cov.: 33

Gnomad AFR AF: 0.00461

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0504

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0306

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0224 AC: 5585 AN: 249332 AF XY: 0.0228

Gnomad AFR exome AF: 0.00407

Gnomad AMR exome AF: 0.0152

Gnomad ASJ exome AF: 0.0492

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.0215

Gnomad NFE exome AF: 0.0316

Gnomad OTH exome AF: 0.0256

GnomAD4 exome AF: 0.0277 AC: 40478 AN: 1460806 Hom.: 676 Cov.: 33 AF XY: 0.0275 AC XY: 19953 AN XY: 726708

African (AFR) AF: 0.00487 AC: 163 AN: 33468

American (AMR) AF: 0.0154 AC: 688 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0527 AC: 1377 AN: 26106

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39688

South Asian (SAS) AF: 0.0117 AC: 1012 AN: 86240

European-Finnish (FIN) AF: 0.0234 AC: 1235 AN: 52744

Middle Eastern (MID) AF: 0.0458 AC: 264 AN: 5764

European-Non Finnish (NFE) AF: 0.0308 AC: 34220 AN: 1111732

Other (OTH) AF: 0.0251 AC: 1517 AN: 60362

GnomAD4 genome AF: 0.0197 AC: 3000 AN: 152362 Hom.: 52 Cov.: 33 AF XY: 0.0190 AC XY: 1415 AN XY: 74502

African (AFR) AF: 0.00459 AC: 191 AN: 41594

American (AMR) AF: 0.0155 AC: 238 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0504 AC: 175 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00787 AC: 38 AN: 4830

European-Finnish (FIN) AF: 0.0188 AC: 200 AN: 10630

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0305 AC: 2078 AN: 68032

Other (OTH) AF: 0.0237 AC: 50 AN: 2114

Alfa AF: 0.0272 Hom.: 12

Bravo AF: 0.0194

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.0
DANN	Benign	0.48
PhyloP100		0.079
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00059
dbscSNV1_RF	Benign	0.014
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: rs78530908; hg19: chr7-100275110;