rs9658668

chr14-92932724-C-T

Variant summary

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

The NM_001275.4(CHGA):c.1163C>T(p.Pro388Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,610,906 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: CHGA NM_001275.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.191

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

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=0.005293399).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHGA	NM_001275.4	c.1163C>T	p.Pro388Leu	missense_variant	7/8	ENST00000216492.10
CHGA	NM_001301690.2	c.710C>T	p.Pro237Leu	missense_variant	6/7
CHGA	XM_011536370.3	c.1163C>T	p.Pro388Leu	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHGA	ENST00000216492.10	c.1163C>T	p.Pro388Leu	missense_variant	7/8	1	NM_001275.4	P1
CHGA	ENST00000334654.4	c.710C>T	p.Pro237Leu	missense_variant	6/7	1
CHGA	ENST00000556876.1	n.381C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000386 AC: 92 AN: 238524 Hom.: 0 AF XY: 0.000398 AC XY: 52 AN XY: 130492

Gnomad AFR exome AF: 0.00423

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00124

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000672

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000848

Gnomad OTH exome AF: 0.000520

GnomAD4 exome AF: 0.000214 AC: 312 AN: 1458666 Hom.: 1 Cov.: 31 AF XY: 0.000197 AC XY: 143 AN XY: 725432

Gnomad4 AFR exome AF: 0.00439

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.00123

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000720

Gnomad4 OTH exome AF: 0.000631

GnomAD4 genome AF: 0.00120 AC: 183 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74446

Gnomad4 AFR AF: 0.00412

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000536 Hom.: 0

Bravo AF: 0.00120

ESP6500AA AF: 0.00320 AC: 14

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000380 AC: 46

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	7.3
Dann	Benign	0.91
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.051	N
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.0053	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.020	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Benign	0.040
Sift	Benign	0.25	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.0050	B;B
Vest4		0.092
MVP		0.34
MPC		0.20
ClinPred		0.0085	T
GERP RS		0.27
Varity_R		0.048
gMVP		0.065

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: rs9658668; hg19: chr14-93399069;