14-92931686-G-C

Variant names:

• chr14-92931686-G-C
• rs9658655
• NM_001275.4:c.792G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001275.4(CHGA):​c.792G>C​(p.Glu264Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,577,272 control chromosomes in the GnomAD database, including 10,297 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1498 hom., cov: 33)
  • Exomes 𝑓: 0.10 (8799 hom.)
• Consequence: CHGA NM_001275.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.804
• Publications: 26 publications found

Genes affected

CHGA (HGNC:1929): (chromogranin A) The protein encoded by this gene is a member of the chromogranin/secretogranin family of neuroendocrine secretory proteins. It is found in secretory vesicles of neurons and endocrine cells. This gene product is a precursor to three biologically active peptides; vasostatin, pancreastatin, and parastatin. These peptides act as autocrine or paracrine negative modulators of the neuroendocrine system. Two other peptides, catestatin and chromofungin, have antimicrobial activity and antifungal activity, respectively. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.003715247).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHGA	NM_001275.4	c.792G>C	p.Glu264Asp	missense_variant	Exon 6 of 8	ENST00000216492.10	NP_001266.1
CHGA	XM_011536370.3	c.792G>C	p.Glu264Asp	missense_variant	Exon 7 of 9		XP_011534672.1
CHGA	NM_001301690.2	c.356-684G>C		intron_variant	Intron 5 of 6		NP_001288619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHGA	ENST00000216492.10	c.792G>C	p.Glu264Asp	missense_variant	Exon 6 of 8	1	NM_001275.4	ENSP00000216492.5

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19220 AN: 152062 Hom.: 1497 Cov.: 33

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.0527

Gnomad EAS AF: 0.246

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.0793

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0808

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.131 AC: 29566 AN: 225826 AF XY: 0.128

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.205

Gnomad ASJ exome AF: 0.0491

Gnomad EAS exome AF: 0.248

Gnomad FIN exome AF: 0.0801

Gnomad NFE exome AF: 0.0809

Gnomad OTH exome AF: 0.0991

GnomAD4 exome AF: 0.101 AC: 143541 AN: 1425092 Hom.: 8799 Cov.: 33 AF XY: 0.102 AC XY: 71615 AN XY: 703606

African (AFR) AF: 0.195 AC: 6371 AN: 32644

American (AMR) AF: 0.197 AC: 8266 AN: 41868

Ashkenazi Jewish (ASJ) AF: 0.0492 AC: 1171 AN: 23798

East Asian (EAS) AF: 0.247 AC: 9662 AN: 39192

South Asian (SAS) AF: 0.182 AC: 14670 AN: 80736

European-Finnish (FIN) AF: 0.0836 AC: 4346 AN: 51998

Middle Eastern (MID) AF: 0.0784 AC: 439 AN: 5600

European-Non Finnish (NFE) AF: 0.0845 AC: 92134 AN: 1090582

Other (OTH) AF: 0.110 AC: 6482 AN: 58674

GnomAD4 genome AF: 0.126 AC: 19250 AN: 152180 Hom.: 1498 Cov.: 33 AF XY: 0.127 AC XY: 9428 AN XY: 74382

African (AFR) AF: 0.191 AC: 7929 AN: 41502

American (AMR) AF: 0.154 AC: 2350 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0527 AC: 183 AN: 3470

East Asian (EAS) AF: 0.244 AC: 1261 AN: 5160

South Asian (SAS) AF: 0.185 AC: 893 AN: 4824

European-Finnish (FIN) AF: 0.0793 AC: 842 AN: 10612

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0807 AC: 5491 AN: 68010

Other (OTH) AF: 0.110 AC: 232 AN: 2104

Alfa AF: 0.0952 Hom.: 180

Bravo AF: 0.135

TwinsUK AF: 0.0920 AC: 341

ALSPAC AF: 0.0906 AC: 349

ESP6500AA AF: 0.180 AC: 791

ESP6500EA AF: 0.0836 AC: 719

ExAC AF: 0.125 AC: 15165

Asia WGS AF: 0.202 AC: 704 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.46	N
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.80
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.097
Sift	Benign	0.089	T
Sift4G	Benign	0.23	T
Polyphen		0.87	P
Vest4		0.035
MutPred		0.099		Gain of MoRF binding (P = 0.1125);
MPC		0.25
ClinPred		0.024	T
GERP RS		4.0
Varity_R		0.086
gMVP		0.076
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9658655; hg19: chr14-93398031; COSMIC: COSV53663370; COSMIC: COSV53663370;