chr10-49625616-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_020549.5(CHAT):​c.896C>G​(p.Pro299Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000313 in 1,594,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P299L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

CHAT
NM_020549.5 missense

Scores

4
13
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.89

Publications

5 publications found
Variant links:
Genes affected
CHAT (HGNC:1912): (choline O-acetyltransferase) This gene encodes an enzyme which catalyzes the biosynthesis of the neurotransmitter acetylcholine. This gene product is a characteristic feature of cholinergic neurons, and changes in these neurons may explain some of the symptoms of Alzheimer's disease. Polymorphisms in this gene have been associated with Alzheimer's disease and mild cognitive impairment. Mutations in this gene are associated with congenital myasthenic syndrome associated with episodic apnea. Multiple transcript variants encoding different isoforms have been found for this gene, and some of these variants have been shown to encode more than one isoform. [provided by RefSeq, May 2010]
CHAT Gene-Disease associations (from GenCC):
  • congenital myasthenic syndrome 6
    Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • presynaptic congenital myasthenic syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHATNM_020549.5 linkc.896C>G p.Pro299Arg missense_variant Exon 6 of 15 ENST00000337653.7 NP_065574.4 P28329-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHATENST00000337653.7 linkc.896C>G p.Pro299Arg missense_variant Exon 6 of 15 1 NM_020549.5 ENSP00000337103.2 P28329-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152224
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000277
AC:
4
AN:
1442744
Hom.:
0
Cov.:
32
AF XY:
0.00000419
AC XY:
3
AN XY:
715662
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33106
American (AMR)
AF:
0.00
AC:
0
AN:
41892
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25680
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39024
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83406
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52110
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5742
European-Non Finnish (NFE)
AF:
0.00000363
AC:
4
AN:
1102100
Other (OTH)
AF:
0.00
AC:
0
AN:
59684
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152224
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74370
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41456
American (AMR)
AF:
0.00
AC:
0
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68042
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
1
Bravo
AF:
0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.47
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Uncertain
0.13
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.54
.;.;.;D;.
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.88
.;.;D;D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.82
D;D;D;D;D
MetaSVM
Uncertain
0.055
D
MutationAssessor
Uncertain
2.3
.;.;.;M;.
PhyloP100
7.9
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-3.8
D;D;D;D;D
REVEL
Pathogenic
0.67
Sift
Uncertain
0.0080
D;D;D;T;T
Sift4G
Benign
0.076
T;T;T;T;T
Polyphen
1.0
.;.;.;D;.
Vest4
0.86
MutPred
0.42
.;.;.;Gain of solvent accessibility (P = 0.0411);.;
MVP
0.89
MPC
0.83
ClinPred
0.99
D
GERP RS
5.3
Varity_R
0.39
gMVP
0.51
Mutation Taster
=61/39
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

Publications

Other links and lift over

dbSNP: rs868749; hg19: chr10-50833662; API