chr14-92932756-C-T

Variant names:

• chr14-92932756-C-T
• rs729940
• NM_001275.4:c.1195C>T

Variant summary

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

The NM_001275.4(CHGA):​c.1195C>T​(p.Arg399Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,605,442 control chromosomes in the GnomAD database, including 18,533 homozygotes. In-silico tool predicts 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R399Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1486 hom., cov: 33)
  • Exomes 𝑓: 0.15 (17047 hom.)
• Consequence: CHGA NM_001275.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.883

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=0.0031467676).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHGA	NM_001275.4	c.1195C>T	p.Arg399Trp	missense_variant	Exon 7 of 8	ENST00000216492.10	NP_001266.1
CHGA	NM_001301690.2	c.742C>T	p.Arg248Trp	missense_variant	Exon 6 of 7		NP_001288619.1
CHGA	XM_011536370.3	c.1195C>T	p.Arg399Trp	missense_variant	Exon 8 of 9		XP_011534672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHGA	ENST00000216492.10	c.1195C>T	p.Arg399Trp	missense_variant	Exon 7 of 8	1	NM_001275.4	ENSP00000216492.5
CHGA	ENST00000334654.4	c.742C>T	p.Arg248Trp	missense_variant	Exon 6 of 7	1		ENSP00000334023.4
CHGA	ENST00000556876.1	n.413C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18714 AN: 152038 Hom.: 1483 Cov.: 33

Gnomad AFR AF: 0.0354

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.0870

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.117

GnomAD2 exomes AF: 0.154 AC: 35476 AN: 229818 AF XY: 0.151

Gnomad AFR exome AF: 0.0309

Gnomad AMR exome AF: 0.270

Gnomad ASJ exome AF: 0.0840

Gnomad EAS exome AF: 0.205

Gnomad FIN exome AF: 0.142

Gnomad NFE exome AF: 0.149

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.149 AC: 216612 AN: 1453284 Hom.: 17047 Cov.: 33 AF XY: 0.147 AC XY: 106220 AN XY: 722078

Gnomad4 AFR exome AF: 0.0290 AC: 970 AN: 33400

Gnomad4 AMR exome AF: 0.257 AC: 11306 AN: 43908

Gnomad4 ASJ exome AF: 0.0856 AC: 2213 AN: 25852

Gnomad4 EAS exome AF: 0.194 AC: 7677 AN: 39492

Gnomad4 SAS exome AF: 0.105 AC: 8937 AN: 84732

Gnomad4 FIN exome AF: 0.142 AC: 7295 AN: 51472

Gnomad4 NFE exome AF: 0.153 AC: 169230 AN: 1108788

Gnomad4 Remaining exome AF: 0.139 AC: 8308 AN: 59972

GnomAD4 genome AF: 0.123 AC: 18720 AN: 152158 Hom.: 1486 Cov.: 33 AF XY: 0.125 AC XY: 9335 AN XY: 74388

Gnomad4 AFR AF: 0.0354 AC: 0.0353686 AN: 0.0353686

Gnomad4 AMR AF: 0.221 AC: 0.220936 AN: 0.220936

Gnomad4 ASJ AF: 0.0870 AC: 0.0869816 AN: 0.0869816

Gnomad4 EAS AF: 0.194 AC: 0.194369 AN: 0.194369

Gnomad4 SAS AF: 0.111 AC: 0.110581 AN: 0.110581

Gnomad4 FIN AF: 0.145 AC: 0.145116 AN: 0.145116

Gnomad4 NFE AF: 0.147 AC: 0.147312 AN: 0.147312

Gnomad4 OTH AF: 0.116 AC: 0.116004 AN: 0.116004

Alfa AF: 0.141 Hom.: 1933

Bravo AF: 0.126

TwinsUK AF: 0.141 AC: 524

ALSPAC AF: 0.155 AC: 598

ESP6500AA AF: 0.0340 AC: 148

ESP6500EA AF: 0.141 AC: 1200

ExAC AF: 0.138 AC: 16625

Asia WGS AF: 0.141 AC: 490 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.19	N
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Benign	0.029
Sift	Uncertain	0.027	D;T
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.063
MPC		0.54
ClinPred		0.045	T
GERP RS		1.2
Varity_R		0.16
gMVP		0.13
Mutation Taster		=98/2	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

Publications

LitVar

Other links and lift over

dbSNP: rs729940; hg19: chr14-93399101; COSMIC: COSV50894455; COSMIC: COSV50894455;