rs742711

Positions:

• chr20-5923394-G-A

Variant summary

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

The NM_001819.3(CHGB):​c.1250G>A​(p.Arg417His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,613,774 control chromosomes in the GnomAD database, including 61,967 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.23 (4809 hom., cov: 31)
  • Exomes 𝑓: 0.28 (57158 hom.)
• Consequence: CHGB NM_001819.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.77

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=9.033978E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHGB	NM_001819.3	c.1250G>A	p.Arg417His	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.1250G>A	p.Arg417His	missense_variant	4/5	1	NM_001819.3	ENSP00000368244.4

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35368 AN: 151916 Hom.: 4803 Cov.: 31

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.128

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.214

GnomAD3 exomes AF: 0.279 AC: 70062 AN: 250998 Hom.: 10559 AF XY: 0.276 AC XY: 37444 AN XY: 135686

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.328

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.387

Gnomad SAS exome AF: 0.258

Gnomad FIN exome AF: 0.364

Gnomad NFE exome AF: 0.272

Gnomad OTH exome AF: 0.253

GnomAD4 exome AF: 0.275 AC: 402435 AN: 1461740 Hom.: 57158 Cov.: 42 AF XY: 0.275 AC XY: 199703 AN XY: 727172

Gnomad4 AFR exome AF: 0.0979

Gnomad4 AMR exome AF: 0.316

Gnomad4 ASJ exome AF: 0.182

Gnomad4 EAS exome AF: 0.396

Gnomad4 SAS exome AF: 0.259

Gnomad4 FIN exome AF: 0.365

Gnomad4 NFE exome AF: 0.275

Gnomad4 OTH exome AF: 0.255

GnomAD4 genome AF: 0.233 AC: 35402 AN: 152034 Hom.: 4809 Cov.: 31 AF XY: 0.236 AC XY: 17574 AN XY: 74314

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.245

Gnomad4 ASJ AF: 0.177

Gnomad4 EAS AF: 0.379

Gnomad4 SAS AF: 0.263

Gnomad4 FIN AF: 0.362

Gnomad4 NFE AF: 0.279

Gnomad4 OTH AF: 0.220

Alfa AF: 0.262 Hom.: 12995

Bravo AF: 0.218

TwinsUK AF: 0.289 AC: 1072

ALSPAC AF: 0.269 AC: 1035

ESP6500AA AF: 0.118 AC: 521

ESP6500EA AF: 0.265 AC: 2277

ExAC AF: 0.273 AC: 33128

Asia WGS AF: 0.338 AC: 1178 AN: 3478

EpiCase AF: 0.258

EpiControl AF: 0.250

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0080
DANN	Benign	0.84
DEOGEN2	Benign	0.036	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.00090	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.27	N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.64	N
REVEL	Benign	0.035
Sift	Benign	0.31	T
Sift4G	Benign	0.24	T
Polyphen		0.013	B
Vest4		0.035
MPC		0.11
ClinPred		0.015	T
GERP RS		-11
Varity_R		0.017
gMVP		0.19

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: rs742711; hg19: chr20-5904040; COSMIC: COSV66759649; COSMIC: COSV66759649;