rs9658668

Variant names:

• chr14-92932724-C-T
• rs9658668
• NM_001275.4:c.1163C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. 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. 15/22 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 0.0012 (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
• Publications: 7 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005293399).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHGA	NM_001275.4	MANE Select	c.1163C>T	p.Pro388Leu	missense	Exon 7 of 8	NP_001266.1
	CHGA	NM_001301690.2		c.710C>T	p.Pro237Leu	missense	Exon 6 of 7	NP_001288619.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHGA	ENST00000216492.10	TSL:1 MANE Select	c.1163C>T	p.Pro388Leu	missense	Exon 7 of 8	ENSP00000216492.5
	CHGA	ENST00000334654.4	TSL:1	c.710C>T	p.Pro237Leu	missense	Exon 6 of 7	ENSP00000334023.4
	CHGA	ENST00000556876.1	TSL:2	n.381C>T		non_coding_transcript_exon	Exon 2 of 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

GnomAD2 exomes AF: 0.000386 AC: 92 AN: 238524 AF XY: 0.000398

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 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

African (AFR) AF: 0.00439 AC: 147 AN: 33464

American (AMR) AF: 0.000269 AC: 12 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 32 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51906

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5708

European-Non Finnish (NFE) AF: 0.0000720 AC: 80 AN: 1111458

Other (OTH) AF: 0.000631 AC: 38 AN: 60182

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

African (AFR) AF: 0.00412 AC: 171 AN: 41548

American (AMR) AF: 0.000261 AC: 4 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2114

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 v4.9

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
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
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.020	N
PhyloP100		0.19
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.040
Sift	Benign	0.25	T
Sift4G	Benign	0.18	T
Polyphen		0.0050	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
Mutation Taster		=96/4	polymorphism

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: rs9658668; hg19: chr14-93399069;