15-52184655-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016194.4(GNB5):c.22G>A(p.Val8Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00364 in 1,613,402 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V8F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0024 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0038 ( 12 hom. )

Consequence

GNB5
NM_016194.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.17

Publications

4 publications found

Variant links:

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 links:

CERNA1 (HGNC:52664): (competing endogenous lncRNA 1 for miR-4707-5p and miR-4767)

CERNA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007861823).

BP6

Variant 15-52184655-C-T is Benign according to our data. Variant chr15-52184655-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 770786.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 = 0.00239 (363/152090) while in subpopulation NFE AF = 0.00377 (256/67990). AF 95% confidence interval is 0.00339. There are 2 homozygotes in GnomAd4. There are 163 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 Unknown,AR gene

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.22G>A	p.Val8Ile	missense	Exon 2 of 13	NP_057278.2
	CERNA1	NR_102751.1		n.529+3453C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GNB5	ENST00000261837.12	TSL:5 MANE Select	c.22G>A	p.Val8Ile	missense	Exon 2 of 13	ENSP00000261837.7	O14775-1
GNB5	ENST00000560075.1	TSL:5	n.53G>A		non_coding_transcript_exon	Exon 2 of 6
CERNA1	ENST00000559779.2	TSL:3	n.1056+3453C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00239

AC:

363

AN:

151972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00376

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.00214

AC:

538

AN:

251284

AF XY:

0.00221

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00358

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00377

AC:

5509

AN:

1461312

Hom.:

Cov.:

AF XY:

0.00366

AC XY:

2661

AN XY:

726976

show subpopulations

African (AFR)

AF:

0.00128

AC:

AN:

33468

American (AMR)

AF:

0.00170

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.000174

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00150

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00458

AC:

5096

AN:

1111556

Other (OTH)

AF:

0.00325

AC:

196

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

235

470

704

939

1174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

206

412

618

824

1030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00239

AC:

363

AN:

152090

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

41480

American (AMR)

AF:

0.00203

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00377

AC:

256

AN:

67990

Other (OTH)

AF:

0.00285

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00301

Hom.:

Bravo

AF:

0.00266

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00296

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00230

AC:

279

EpiCase

AF:

0.00387

EpiControl

AF:

0.00385

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

GNB5-related disorder (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.082

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.64

M_CAP

Benign

0.012

MetaRNN

Benign

0.0079

MetaSVM

Benign

-1.0

PhyloP100

5.2

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.18

REVEL

Benign

0.083

Sift

Benign

0.062

Sift4G

Benign

0.12

Polyphen

0.012

Vest4

0.26

MVP

0.59

MPC

0.32

ClinPred

0.060

GERP RS

5.6

Varity_R

0.045

gMVP

0.085

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over