rs75262191

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_020549.5(CHAT):​c.1087G>A​(p.Glu363Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000555 in 1,613,928 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00057 ( 1 hom. )

Consequence

CHAT
NM_020549.5 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 3.63
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.033172876).
BP6
Variant 10-49627761-G-A is Benign according to our data. Variant chr10-49627761-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 422447.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CHATNM_020549.5 linkuse as main transcriptc.1087G>A p.Glu363Lys missense_variant 7/15 ENST00000337653.7 NP_065574.4 P28329-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CHATENST00000337653.7 linkuse as main transcriptc.1087G>A p.Glu363Lys missense_variant 7/151 NM_020549.5 ENSP00000337103.2 P28329-1

Frequencies

GnomAD3 genomes
AF:
0.000368
AC:
56
AN:
152234
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000523
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000559
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000386
AC:
97
AN:
251054
Hom.:
0
AF XY:
0.000413
AC XY:
56
AN XY:
135722
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000636
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.0000464
Gnomad NFE exome
AF:
0.000564
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000574
AC:
839
AN:
1461576
Hom.:
1
Cov.:
32
AF XY:
0.000553
AC XY:
402
AN XY:
727108
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.000604
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000151
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000685
Gnomad4 OTH exome
AF:
0.000513
GnomAD4 genome
AF:
0.000368
AC:
56
AN:
152352
Hom.:
0
Cov.:
33
AF XY:
0.000389
AC XY:
29
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.000144
Gnomad4 AMR
AF:
0.000523
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000559
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000673
Hom.:
0
Bravo
AF:
0.000453
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000420
AC:
51
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00104
EpiControl
AF:
0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial infantile myasthenia Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 16, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityOct 07, 2019- -
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 18, 2017- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 04, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.20
.;.;.;T;.
Eigen
Benign
-0.44
Eigen_PC
Benign
-0.23
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.90
.;.;D;D;D
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.033
T;T;T;T;T
MetaSVM
Benign
-0.68
T
MutationAssessor
Benign
0.81
.;.;.;L;.
PrimateAI
Benign
0.32
T
PROVEAN
Benign
0.080
N;N;N;N;N
REVEL
Benign
0.19
Sift
Benign
1.0
T;T;T;T;T
Sift4G
Benign
1.0
T;T;T;T;T
Polyphen
0.028
.;.;.;B;.
Vest4
0.44
MVP
0.89
MPC
0.28
ClinPred
0.024
T
GERP RS
2.3
Varity_R
0.13
gMVP
0.43

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs75262191; hg19: chr10-50835807; API