20-5916917-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001819.3(CHGB):​c.188C>T​(p.Thr63Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

CHGB
NM_001819.3 missense, splice_region

Scores

3
16
Splicing: ADA: 0.01793
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.58
Variant links:
Genes affected
CHGB (HGNC:1930): (chromogranin B) This gene encodes a tyrosine-sulfated secretory protein abundant in peptidergic endocrine cells and neurons. This protein may serve as a precursor for regulatory peptides. [provided by RefSeq, Jan 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06106496).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHGBNM_001819.3 linkc.188C>T p.Thr63Met missense_variant, splice_region_variant Exon 3 of 5 ENST00000378961.9 NP_001810.2 P05060

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHGBENST00000378961.9 linkc.188C>T p.Thr63Met missense_variant, splice_region_variant Exon 3 of 5 1 NM_001819.3 ENSP00000368244.4 P05060
CHGBENST00000455042.1 linkc.128C>T p.Thr43Met missense_variant, splice_region_variant Exon 4 of 5 3 ENSP00000416643.1 A0A0A0MT66
CHGBENST00000488832.1 linkn.967C>T non_coding_transcript_exon_variant Exon 2 of 2 2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152162
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251378
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135866
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.0000578
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:
0.0000616
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000219
AC:
32
AN:
1461762
Hom.:
0
Cov.:
31
AF XY:
0.0000234
AC XY:
17
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000216
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152280
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000289
Hom.:
0
Bravo
AF:
0.0000227
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000412
AC:
5
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 31, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.188C>T (p.T63M) alteration is located in exon 3 (coding exon 3) of the CHGB gene. This alteration results from a C to T substitution at nucleotide position 188, causing the threonine (T) at amino acid position 63 to be replaced by a methionine (M). 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
Benign
0.10
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.093
T;T
Eigen
Benign
-0.26
Eigen_PC
Benign
-0.16
FATHMM_MKL
Benign
0.71
D
LIST_S2
Benign
0.77
T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.061
T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
0.34
N;.
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.42
N;N
REVEL
Benign
0.069
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.032
D;T
Polyphen
0.81
P;.
Vest4
0.35
MVP
0.34
MPC
0.22
ClinPred
0.18
T
GERP RS
2.2
Varity_R
0.076
gMVP
0.14

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.018
dbscSNV1_RF
Benign
0.21
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs143107119; hg19: chr20-5897563; COSMIC: COSV66760740; API