20-5922578-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001819.3(CHGB):c.434A>G(p.Asp145Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D145N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: CHGB NM_001819.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04479724).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHGB	NM_001819.3	c.434A>G	p.Asp145Gly	missense_variant	4/5	ENST00000378961.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHGB	ENST00000378961.9	c.434A>G	p.Asp145Gly	missense_variant	4/5	1	NM_001819.3	P1
CHGB	ENST00000455042.1	c.374A>G	p.Asp125Gly	missense_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000519 AC: 13 AN: 250492 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461738 Hom.: 0 Cov.: 59 AF XY: 0.00000963 AC XY: 7 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2021

The c.434A>G (p.D145G) alteration is located in exon 4 (coding exon 4) of the CHGB gene. This alteration results from a A to G substitution at nucleotide position 434, causing the aspartic acid (D) at amino acid position 145 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	9.6
Dann	Benign	0.34
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.56	N;N
REVEL	Benign	0.039
Sift	Benign	0.41	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.0	B;.
Vest4		0.052
MutPred		0.28		Gain of MoRF binding (P = 0.0469);.;
MVP		0.23
MPC		0.11
ClinPred		0.037	T
GERP RS		1.2
Varity_R		0.045
gMVP		0.16

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: rs750417629; hg19: chr20-5903224;