chr10-49622125-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020549.5(CHAT):c.727C>T(p.Leu243Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0566 in 1,610,118 control chromosomes in the GnomAD database, including 3,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.046 ( 253 hom., cov: 33)

Exomes 𝑓: 0.058 ( 2826 hom. )

Consequence

CHAT
NM_020549.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.05

Publications

31 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

CHAT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003634721).

BP6

Variant 10-49622125-C-T is Benign according to our data. Variant chr10-49622125-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5 link	c.727C>T	p.Leu243Phe	missense_variant	Exon 5 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.727C>T	p.Leu243Phe	missense_variant	Exon 5 of 15	1	NM_020549.5	ENSP00000337103.2		P28329-1

Frequencies

GnomAD3 genomes

AF:

0.0458

AC:

6933

AN:

151280

Hom.:

253

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0101

Gnomad AMI

AF:

0.0960

Gnomad AMR

AF:

0.0307

Gnomad ASJ

AF:

0.0607

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0131

Gnomad FIN

AF:

0.110

Gnomad MID

AF:

0.0194

Gnomad NFE

AF:

0.0658

Gnomad OTH

AF:

0.0352

GnomAD2 exomes

AF:

0.0468

AC:

11764

AN:

251386

AF XY:

0.0462

show subpopulations

Gnomad AFR exome

AF:

0.00855

Gnomad AMR exome

AF:

0.0227

Gnomad ASJ exome

AF:

0.0555

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.112

Gnomad NFE exome

AF:

0.0635

Gnomad OTH exome

AF:

0.0484

GnomAD4 exome

AF:

0.0577

AC:

84233

AN:

1458722

Hom.:

2826

Cov.:

AF XY:

0.0566

AC XY:

41108

AN XY:

725782

show subpopulations

African (AFR)

AF:

0.00796

AC:

266

AN:

33406

American (AMR)

AF:

0.0210

AC:

935

AN:

44434

Ashkenazi Jewish (ASJ)

AF:

0.0549

AC:

1424

AN:

25944

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39664

South Asian (SAS)

AF:

0.0126

AC:

1087

AN:

86168

European-Finnish (FIN)

AF:

0.108

AC:

5725

AN:

53152

Middle Eastern (MID)

AF:

0.0167

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0644

AC:

71505

AN:

1109974

Other (OTH)

AF:

0.0530

AC:

3193

AN:

60230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

4299

8598

12896

17195

21494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0458

AC:

6932

AN:

151396

Hom.:

253

Cov.:

AF XY:

0.0466

AC XY:

3449

AN XY:

74012

show subpopulations

African (AFR)

AF:

0.0101

AC:

415

AN:

41212

American (AMR)

AF:

0.0307

AC:

466

AN:

15202

Ashkenazi Jewish (ASJ)

AF:

0.0607

AC:

210

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.0133

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.110

AC:

1153

AN:

10500

Middle Eastern (MID)

AF:

0.0174

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0658

AC:

4459

AN:

67770

Other (OTH)

AF:

0.0348

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

344

687

1031

1374

1718

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0547

Hom.:

1290

Bravo

AF:

0.0376

TwinsUK

AF:

0.0620

AC:

230

ALSPAC

AF:

0.0649

AC:

250

ESP6500AA

AF:

0.0111

AC:

ESP6500EA

AF:

0.0635

AC:

546

ExAC

AF:

0.0466

AC:

5663

Asia WGS

AF:

0.00924

AC:

AN:

3476

EpiCase

AF:

0.0600

EpiControl

AF:

0.0602

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Dec 26, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 19, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 24, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial infantile myasthenia

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

.;.;.;D;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.93

.;.;D;D;D

MetaRNN

Benign

0.0036

T;T;T;T;T

MetaSVM

Benign

-0.29

MutationAssessor

Pathogenic

2.9

.;.;.;M;.

PhyloP100

4.1

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.3

D;D;D;D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0030

D;D;D;D;D

Sift4G

Uncertain

0.0090

D;D;D;D;D

Polyphen

1.0

.;.;.;D;.

Vest4

0.30

MPC

0.93

ClinPred

0.030

GERP RS

4.7

Varity_R

0.69

gMVP

0.58

Mutation Taster

=88/12

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr10-49622125-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over