NM_001275.4:c.938C>T

Variant names:

• chr14-92932499-C-T
• rs904123149
• NM_001275.4:c.938C>T

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.938C>T​(p.Pro313Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,554,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: CHGA NM_001275.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.36
• 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: 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=0.18510213).

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.938C>T	p.Pro313Leu	missense	Exon 7 of 8	NP_001266.1	P10645
	CHGA	NM_001301690.2		c.485C>T	p.Pro162Leu	missense	Exon 6 of 7	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.938C>T	p.Pro313Leu	missense	Exon 7 of 8	ENSP00000216492.5	P10645
	CHGA	ENST00000334654.4	TSL:1	c.485C>T	p.Pro162Leu	missense	Exon 6 of 7	ENSP00000334023.4	G5E968
	CHGA	ENST00000903324.1		c.968C>T	p.Pro323Leu	missense	Exon 7 of 8	ENSP00000573383.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151936 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000249 AC: 4 AN: 160544 AF XY: 0.0000237

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000802

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000317

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 49 AN: 1402160 Hom.: 0 Cov.: 30 AF XY: 0.0000361 AC XY: 25 AN XY: 691830

African (AFR) AF: 0.00 AC: 0 AN: 31930

American (AMR) AF: 0.0000558 AC: 2 AN: 35870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25198

East Asian (EAS) AF: 0.00 AC: 0 AN: 36250

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49206

Middle Eastern (MID) AF: 0.000379 AC: 2 AN: 5278

European-Non Finnish (NFE) AF: 0.0000389 AC: 42 AN: 1080850

Other (OTH) AF: 0.0000344 AC: 2 AN: 58174

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151936 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74206

African (AFR) AF: 0.0000242 AC: 1 AN: 41342

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

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	0.10
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.15	N
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.4
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.093
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.015	D
Polyphen		0.51	P
Vest4		0.23
MutPred		0.60		Gain of helix (P = 0.0078)
MVP		0.44
MPC		0.69
ClinPred		0.65	D
GERP RS		3.9
Varity_R		0.11
gMVP		0.14
Mutation Taster		=89/11	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: rs904123149; hg19: chr14-93398844;