NM_001275.4:c.139C>T

Variant names:

• chr14-92926650-C-T
• rs767658123
• NM_001275.4:c.139C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001275.4(CHGA):​c.139C>T​(p.Pro47Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHGA NM_001275.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.25

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHGA	NM_001275.4	c.139C>T	p.Pro47Ser	missense_variant	Exon 3 of 8	ENST00000216492.10	NP_001266.1
CHGA	NM_001301690.2	c.139C>T	p.Pro47Ser	missense_variant	Exon 3 of 7		NP_001288619.1
CHGA	XM_011536370.3	c.139C>T	p.Pro47Ser	missense_variant	Exon 4 of 9		XP_011534672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHGA	ENST00000216492.10	c.139C>T	p.Pro47Ser	missense_variant	Exon 3 of 8	1	NM_001275.4	ENSP00000216492.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.139C>T (p.P47S) alteration is located in exon 3 (coding exon 3) of the CHGA gene. This alteration results from a C to T substitution at nucleotide position 139, causing the proline (P) at amino acid position 47 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		1.0	D;D
Vest4		0.63
MutPred		0.42		Gain of phosphorylation at P47 (P = 0.0369);Gain of phosphorylation at P47 (P = 0.0369);
MVP		0.51
MPC		0.78
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.83
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs767658123; hg19: chr14-93392995;