Genetic Variant CHGB:p.Ala353Gly (chr20-5923202-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001819.3(CHGB):c.1058C>G(p.Ala353Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.401 in 1,613,684 control chromosomes in the GnomAD database, including 135,342 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A353T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.47 ( 17600 hom., cov: 31)

Exomes 𝑓: 0.39 ( 117742 hom. )

Consequence

CHGB
NM_001819.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.420

Publications

35 publications found

Variant links:

Genes affected

CHGB (HGNC:1930): (chromogranin B) This gene encodes a tyrosine-sulfated secretory protein abundant in peptidergic endocrine cells and neurons. This protein may serve as a precursor for regulatory peptides. [provided by RefSeq, Jan 2009]

CHGB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=1.9415429E-5).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHGB	NM_001819.3 link	c.1058C>G	p.Ala353Gly	missense_variant	Exon 4 of 5	ENST00000378961.9	NP_001810.2	P05060

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHGB	ENST00000378961.9 link	c.1058C>G	p.Ala353Gly	missense_variant	Exon 4 of 5	1	NM_001819.3	ENSP00000368244.4		P05060
CHGB	ENST00000455042.1 link	c.*129C>G		downstream_gene_variant		3		ENSP00000416643.1		A0A0A0MT66

Frequencies

GnomAD3 genomes

AF:

0.466

AC:

70749

AN:

151736

Hom.:

17566

Cov.:

show subpopulations

Gnomad AFR

AF:

0.626

Gnomad AMI

AF:

0.365

Gnomad AMR

AF:

0.507

Gnomad ASJ

AF:

0.285

Gnomad EAS

AF:

0.542

Gnomad SAS

AF:

0.456

Gnomad FIN

AF:

0.416

Gnomad MID

AF:

0.330

Gnomad NFE

AF:

0.375

Gnomad OTH

AF:

0.429

GnomAD2 exomes

AF:

0.449

AC:

112629

AN:

251100

AF XY:

0.435

show subpopulations

Gnomad AFR exome

AF:

0.628

Gnomad AMR exome

AF:

0.635

Gnomad ASJ exome

AF:

0.288

Gnomad EAS exome

AF:

0.558

Gnomad FIN exome

AF:

0.415

Gnomad NFE exome

AF:

0.373

Gnomad OTH exome

AF:

0.403

GnomAD4 exome

AF:

0.395

AC:

576852

AN:

1461828

Hom.:

117742

Cov.:

AF XY:

0.394

AC XY:

286703

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.627

AC:

20998

AN:

33480

American (AMR)

AF:

0.620

AC:

27715

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.284

AC:

7435

AN:

26136

East Asian (EAS)

AF:

0.533

AC:

21157

AN:

39700

South Asian (SAS)

AF:

0.438

AC:

37820

AN:

86258

European-Finnish (FIN)

AF:

0.418

AC:

22344

AN:

53396

Middle Eastern (MID)

AF:

0.367

AC:

2119

AN:

5768

European-Non Finnish (NFE)

AF:

0.372

AC:

413244

AN:

1111972

Other (OTH)

AF:

0.398

AC:

24020

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

21529

43059

64588

86118

107647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13326

26652

39978

53304

66630

<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:

0.467

AC:

70841

AN:

151856

Hom.:

17600

Cov.:

AF XY:

0.469

AC XY:

34821

AN XY:

74204

show subpopulations

African (AFR)

AF:

0.626

AC:

25917

AN:

41416

American (AMR)

AF:

0.507

AC:

7745

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.285

AC:

988

AN:

3464

East Asian (EAS)

AF:

0.542

AC:

2789

AN:

5150

South Asian (SAS)

AF:

0.455

AC:

2187

AN:

4802

European-Finnish (FIN)

AF:

0.416

AC:

4381

AN:

10538

Middle Eastern (MID)

AF:

0.341

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.375

AC:

25492

AN:

67914

Other (OTH)

AF:

0.433

AC:

911

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1823

3645

5468

7290

9113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

640

1280

1920

2560

3200

<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:

0.389

Hom.:

9111

Bravo

AF:

0.479

TwinsUK

AF:

0.377

AC:

1398

ALSPAC

AF:

0.367

AC:

1413

ESP6500AA

AF:

0.621

AC:

2735

ESP6500EA

AF:

0.359

AC:

3091

ExAC

AF:

0.445

AC:

53995

Asia WGS

AF:

0.544

AC:

1893

AN:

3476

EpiCase

AF:

0.366

EpiControl

AF:

0.363

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.21

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.046

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.27

MetaRNN

Benign

0.000019

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

-0.42

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.040

REVEL

Benign

0.021

Sift

Benign

0.50

Sift4G

Benign

0.77

Polyphen

0.0

Vest4

0.057

MPC

0.15

ClinPred

0.0039

GERP RS

-1.1

Varity_R

0.026

gMVP

0.19

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over