rs80097077

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020549.5(CHAT):c.1682G>A(p.Arg561Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0096 in 1,614,060 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0098 ( 78 hom. )

Consequence

CHAT
NM_020549.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 8.02

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025550604).

BP6

Variant 10-49655142-G-A is Benign according to our data. Variant chr10-49655142-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49655142-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00811 (1235/152238) while in subpopulation AMR AF= 0.0155 (237/15288). AF 95% confidence interval is 0.0139. There are 9 homozygotes in gnomad4. There are 607 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5 link	c.1682G>A	p.Arg561Gln	missense_variant	Exon 12 of 15	ENST00000337653.7	NP_065574.4	P28329-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7 link	c.1682G>A	p.Arg561Gln	missense_variant	Exon 12 of 15	1	NM_020549.5	ENSP00000337103.2		P28329-1

Frequencies

GnomAD3 genomes

AF:

0.00812

AC:

1235

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00256

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0155

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00669

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0111

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00750

AC:

1885

AN:

251288

Hom.:

AF XY:

0.00751

AC XY:

1020

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00997

Gnomad ASJ exome

AF:

0.00992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.00725

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.00946

GnomAD4 exome

AF:

0.00976

AC:

14264

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00947

AC XY:

6890

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00164

Gnomad4 AMR exome

AF:

0.0104

Gnomad4 ASJ exome

AF:

0.00830

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.00826

Gnomad4 NFE exome

AF:

0.0113

Gnomad4 OTH exome

AF:

0.00800

GnomAD4 genome

AF:

0.00811

AC:

1235

AN:

152238

Hom.:

Cov.:

AF XY:

0.00816

AC XY:

607

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00255

Gnomad4 AMR

AF:

0.0155

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00669

Gnomad4 NFE

AF:

0.0111

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.00974

Hom.:

Bravo

AF:

0.00802

TwinsUK

AF:

0.0132

AC:

ALSPAC

AF:

0.0130

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0102

AC:

ExAC

AF:

0.00743

AC:

902

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0110

EpiControl

AF:

0.0127

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Familial infantile myasthenia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

.;.;.;D;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;.;D;D;D;D

MetaRNN

Benign

0.026

T;T;T;T;T;T

MetaSVM

Uncertain

0.29

MutationAssessor

Uncertain

2.2

.;.;.;M;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.8

D;D;D;D;D;.

REVEL

Pathogenic

0.71

Sift

Benign

0.040

D;D;D;D;D;.

Sift4G

Benign

0.069

T;T;T;D;T;.

Polyphen

1.0

.;.;.;D;.;.

Vest4

0.66

MVP

0.96

MPC

0.96

ClinPred

0.0077

GERP RS

5.4

Varity_R

0.75

gMVP

0.78

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over