20-5922871-A-G

Position:

• chr20-5922871-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001819.3(CHGB):​c.727A>G​(p.Thr243Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 1,613,678 control chromosomes in the GnomAD database, including 476,687 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.82 (51040 hom., cov: 30)
  • Exomes 𝑓: 0.76 (425647 hom.)
• Consequence: CHGB NM_001819.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.337

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3750732E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHGB	NM_001819.3	c.727A>G	p.Thr243Ala	missense_variant	4/5	ENST00000378961.9	NP_001810.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHGB	ENST00000378961.9	c.727A>G	p.Thr243Ala	missense_variant	4/5	1	NM_001819.3	ENSP00000368244.4
CHGB	ENST00000455042.1	c.667A>G	p.Thr223Ala	missense_variant	5/5	3		ENSP00000416643.1

Frequencies

GnomAD3 genomes AF: 0.815 AC: 123848 AN: 151964 Hom.: 50985 Cov.: 30

Gnomad AFR AF: 0.913

Gnomad AMI AF: 0.727

Gnomad AMR AF: 0.813

Gnomad ASJ AF: 0.729

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.773

Gnomad FIN AF: 0.843

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.747

Gnomad OTH AF: 0.806

GnomAD3 exomes AF: 0.803 AC: 200231 AN: 249462 Hom.: 81199 AF XY: 0.793 AC XY: 107301 AN XY: 135232

Gnomad AFR exome AF: 0.915

Gnomad AMR exome AF: 0.847

Gnomad ASJ exome AF: 0.731

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.769

Gnomad FIN exome AF: 0.831

Gnomad NFE exome AF: 0.752

Gnomad OTH exome AF: 0.780

GnomAD4 exome AF: 0.761 AC: 1112180 AN: 1461596 Hom.: 425647 Cov.: 60 AF XY: 0.760 AC XY: 552776 AN XY: 727068

Gnomad4 AFR exome AF: 0.915

Gnomad4 AMR exome AF: 0.843

Gnomad4 ASJ exome AF: 0.733

Gnomad4 EAS exome AF: 0.998

Gnomad4 SAS exome AF: 0.767

Gnomad4 FIN exome AF: 0.828

Gnomad4 NFE exome AF: 0.741

Gnomad4 OTH exome AF: 0.770

GnomAD4 genome AF: 0.815 AC: 123960 AN: 152082 Hom.: 51040 Cov.: 30 AF XY: 0.820 AC XY: 60941 AN XY: 74322

Gnomad4 AFR AF: 0.913

Gnomad4 AMR AF: 0.813

Gnomad4 ASJ AF: 0.729

Gnomad4 EAS AF: 0.996

Gnomad4 SAS AF: 0.772

Gnomad4 FIN AF: 0.843

Gnomad4 NFE AF: 0.747

Gnomad4 OTH AF: 0.808

Alfa AF: 0.761 Hom.: 109041

Bravo AF: 0.820

ESP6500AA AF: 0.907 AC: 3997

ESP6500EA AF: 0.743 AC: 6388

ExAC AF: 0.802 AC: 97324

Asia WGS AF: 0.903 AC: 3140 AN: 3478

EpiCase AF: 0.741

EpiControl AF: 0.738

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.033
DANN	Benign	0.49
DEOGEN2	Benign	0.063	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.20	T;T
MetaRNN	Benign	0.0000014	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.018
Sift	Benign	0.56	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.0	B;.
Vest4		0.0090
MPC		0.082
ClinPred		0.0039	T
GERP RS		-3.9
Varity_R		0.034
gMVP		0.11

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

LitVar

Other links and lift over

dbSNP: rs236151; hg19: chr20-5903517;