chr14-92929779-G-C

Variant names:

• chr14-92929779-G-C
• rs539889244
• NM_001275.4:c.319G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001275.4(CHGA):​c.319G>C​(p.Val107Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHGA NM_001275.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.69

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29176068).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHGA	NM_001275.4	c.319G>C	p.Val107Leu	missense_variant	Exon 5 of 8	ENST00000216492.10	NP_001266.1
CHGA	NM_001301690.2	c.319G>C	p.Val107Leu	missense_variant	Exon 5 of 7		NP_001288619.1
CHGA	XM_011536370.3	c.319G>C	p.Val107Leu	missense_variant	Exon 6 of 9		XP_011534672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHGA	ENST00000216492.10	c.319G>C	p.Val107Leu	missense_variant	Exon 5 of 8	1	NM_001275.4	ENSP00000216492.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250260 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135558

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461028 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726776

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T;T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.090
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.046	D;T
Polyphen		0.94	P;P
Vest4		0.41
MutPred		0.39		Gain of solvent accessibility (P = 0.0086);Gain of solvent accessibility (P = 0.0086);
MVP		0.33
MPC		0.20
ClinPred		0.50	D
GERP RS		4.6
Varity_R		0.20
gMVP		0.22

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: rs539889244; hg19: chr14-93396124;