chr14-92931498-G-C

Variant names:

• chr14-92931498-G-C
• rs578186826
• NM_001275.4:c.604G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001275.4(CHGA):​c.604G>C​(p.Asp202His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CHGA NM_001275.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.238
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10846424).

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.604G>C	p.Asp202His	missense	Exon 6 of 8	NP_001266.1	P10645
	CHGA	NM_001301690.2		c.356-872G>C		intron	N/A	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.604G>C	p.Asp202His	missense	Exon 6 of 8	ENSP00000216492.5	P10645
	CHGA	ENST00000334654.4	TSL:1	c.356-872G>C		intron	N/A	ENSP00000334023.4	G5E968
	CHGA	ENST00000903324.1		c.634G>C	p.Asp212His	missense	Exon 6 of 8	ENSP00000573383.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152090 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000162 AC: 4 AN: 246956 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000220

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460356 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726326

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26034

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111634

Other (OTH) AF: 0.00 AC: 0 AN: 60338

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74424

African (AFR) AF: 0.00 AC: 0 AN: 41526

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.017
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.12	N
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.24
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.087
Sift	Benign	0.11	T
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.13
MutPred		0.36		Gain of catalytic residue at D202 (P = 0.0864)
MVP		0.33
MPC		0.83
ClinPred		0.43	T
GERP RS		4.0
Varity_R		0.10
gMVP		0.22
Mutation Taster		=85/15	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: rs578186826; hg19: chr14-93397843;