rs9658667

Variant names:

• chr14-92932705-G-A
• rs9658667
• NM_001275.4:c.1144G>A

Variant summary

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

The NM_001275.4(CHGA):​c.1144G>A​(p.Gly382Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0333 in 1,611,068 control chromosomes in the GnomAD database, including 1,096 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.

• Frequency:
  • Genomes: 𝑓 0.024 (65 hom., cov: 32)
  • Exomes 𝑓: 0.034 (1031 hom.)
• Consequence: CHGA NM_001275.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.16
• Publications: 25 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=0.0028131306).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0566 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001275.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHGA	NM_001275.4	MANE Select	c.1144G>A	p.Gly382Ser	missense	Exon 7 of 8	NP_001266.1	P10645
	CHGA	NM_001301690.2		c.691G>A	p.Gly231Ser	missense	Exon 6 of 7	NP_001288619.1	G5E968

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHGA	ENST00000216492.10	TSL:1 MANE Select	c.1144G>A	p.Gly382Ser	missense	Exon 7 of 8	ENSP00000216492.5	P10645
	CHGA	ENST00000334654.4	TSL:1	c.691G>A	p.Gly231Ser	missense	Exon 6 of 7	ENSP00000334023.4	G5E968
	CHGA	ENST00000903324.1		c.1174G>A	p.Gly392Ser	missense	Exon 7 of 8	ENSP00000573383.1

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 3633 AN: 152118 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.00596

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.0537

Gnomad SAS AF: 0.0626

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0330

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.0314 AC: 7517 AN: 239082 AF XY: 0.0336

Gnomad AFR exome AF: 0.00639

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.0316

Gnomad EAS exome AF: 0.0558

Gnomad FIN exome AF: 0.0161

Gnomad NFE exome AF: 0.0317

Gnomad OTH exome AF: 0.0250

GnomAD4 exome AF: 0.0343 AC: 50058 AN: 1458832 Hom.: 1031 Cov.: 31 AF XY: 0.0352 AC XY: 25555 AN XY: 725528

African (AFR) AF: 0.00493 AC: 165 AN: 33472

American (AMR) AF: 0.0128 AC: 573 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.0326 AC: 850 AN: 26042

East Asian (EAS) AF: 0.0621 AC: 2463 AN: 39672

South Asian (SAS) AF: 0.0606 AC: 5197 AN: 85704

European-Finnish (FIN) AF: 0.0175 AC: 906 AN: 51808

Middle Eastern (MID) AF: 0.0202 AC: 116 AN: 5730

European-Non Finnish (NFE) AF: 0.0339 AC: 37710 AN: 1111554

Other (OTH) AF: 0.0345 AC: 2078 AN: 60238

GnomAD4 genome AF: 0.0238 AC: 3628 AN: 152236 Hom.: 65 Cov.: 32 AF XY: 0.0235 AC XY: 1751 AN XY: 74430

African (AFR) AF: 0.00594 AC: 247 AN: 41548

American (AMR) AF: 0.0160 AC: 245 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3472

East Asian (EAS) AF: 0.0536 AC: 277 AN: 5164

South Asian (SAS) AF: 0.0624 AC: 301 AN: 4824

European-Finnish (FIN) AF: 0.0123 AC: 131 AN: 10612

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0330 AC: 2246 AN: 67986

Other (OTH) AF: 0.0255 AC: 54 AN: 2116

Alfa AF: 0.0307 Hom.: 140

Bravo AF: 0.0232

TwinsUK AF: 0.0332 AC: 123

ALSPAC AF: 0.0330 AC: 127

ESP6500AA AF: 0.00594 AC: 26

ESP6500EA AF: 0.0286 AC: 245

ExAC AF: 0.0308 AC: 3729

Asia WGS AF: 0.0420 AC: 146 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.18	N
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.095
Sift	Benign	0.050	D
Sift4G	Benign	0.28	T
Polyphen		0.53	P
Vest4		0.048
MPC		0.29
ClinPred		0.022	T
GERP RS		4.8
Varity_R		0.073
gMVP		0.11
Mutation Taster		=92/8	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: rs9658667; hg19: chr14-93399050; COSMIC: COSV107244692; COSMIC: COSV107244692;