10-49648606-G-A

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.1381G>A(p.Val461Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.994 in 1,609,818 control chromosomes in the GnomAD database, including 795,386 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V461A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.97 ( 71526 hom., cov: 32)

Exomes 𝑓: 1.0 ( 723860 hom. )

Consequence

CHAT
NM_020549.5 missense, splice_region

Scores

Splicing: ADA: 0.00002959

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.30

Publications

28 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=6.5965037E-7).

BP6

Variant 10-49648606-G-A is Benign according to our data. Variant chr10-49648606-G-A is described in CliVar as Benign. Clinvar id is 199157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49648606-G-A is described in CliVar as Benign. Clinvar id is 199157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49648606-G-A is described in CliVar as Benign. Clinvar id is 199157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49648606-G-A is described in CliVar as Benign. Clinvar id is 199157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49648606-G-A is described in CliVar as Benign. Clinvar id is 199157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49648606-G-A is described in CliVar as Benign. Clinvar id is 199157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49648606-G-A is described in CliVar as Benign. Clinvar id is 199157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49648606-G-A is described in CliVar as Benign. Clinvar id is 199157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49648606-G-A is described in CliVar as Benign. Clinvar id is 199157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49648606-G-A is described in CliVar as Benign. Clinvar id is 199157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49648606-G-A is described in CliVar as Benign. Clinvar id is 199157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49648606-G-A is described in CliVar as Benign. Clinvar id is 199157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49648606-G-A is described in CliVar as Benign. Clinvar id is 199157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5 link	c.1381G>A	p.Val461Met	missense_variant, splice_region_variant	Exon 9 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.1381G>A	p.Val461Met	missense_variant, splice_region_variant	Exon 9 of 15	1	NM_020549.5	ENSP00000337103.2		P28329-1

Frequencies

GnomAD3 genomes

AF:

0.968

AC:

147239

AN:

152126

Hom.:

71478

Cov.:

show subpopulations

Gnomad AFR

AF:

0.887

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.991

Gnomad ASJ

AF:

0.998

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.979

GnomAD2 exomes

AF:

0.991

AC:

246545

AN:

248716

AF XY:

0.994

show subpopulations

Gnomad AFR exome

AF:

0.884

Gnomad AMR exome

AF:

0.993

Gnomad ASJ exome

AF:

0.999

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.995

GnomAD4 exome

AF:

0.996

AC:

1452385

AN:

1457574

Hom.:

723860

Cov.:

AF XY:

0.997

AC XY:

722972

AN XY:

725220

show subpopulations

African (AFR)

AF:

0.882

AC:

29425

AN:

33366

American (AMR)

AF:

0.993

AC:

44340

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.999

AC:

26086

AN:

26112

East Asian (EAS)

AF:

1.00

AC:

39664

AN:

39664

South Asian (SAS)

AF:

1.00

AC:

85846

AN:

85864

European-Finnish (FIN)

AF:

1.00

AC:

53217

AN:

53218

Middle Eastern (MID)

AF:

0.992

AC:

5711

AN:

5758

European-Non Finnish (NFE)

AF:

1.00

AC:

1108303

AN:

1108708

Other (OTH)

AF:

0.993

AC:

59793

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

237

474

710

947

1184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21584

43168

64752

86336

107920

<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:

0.968

AC:

147345

AN:

152244

Hom.:

71526

Cov.:

AF XY:

0.969

AC XY:

72135

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.887

AC:

36803

AN:

41482

American (AMR)

AF:

0.991

AC:

15172

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.998

AC:

3463

AN:

3470

East Asian (EAS)

AF:

1.00

AC:

5170

AN:

5170

South Asian (SAS)

AF:

1.00

AC:

4826

AN:

4826

European-Finnish (FIN)

AF:

1.00

AC:

10620

AN:

10620

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68016

AN:

68048

Other (OTH)

AF:

0.980

AC:

2069

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

207

413

620

826

1033

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

912

1824

2736

3648

4560

<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:

0.989

Hom.:

196436

Bravo

AF:

0.963

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3853

ESP6500AA

AF:

0.886

AC:

3905

ESP6500EA

AF:

0.999

AC:

8594

ExAC

AF:

0.989

AC:

120061

Asia WGS

AF:

0.994

AC:

3456

AN:

3478

EpiCase

AF:

0.999

EpiControl

AF:

0.999

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial infantile myasthenia

Benign:3

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

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 -

Nov 21, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.077

DEOGEN2

Benign

0.18

.;.;.;T;.;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.17

.;.;T;T;T;T

MetaRNN

Benign

6.6e-7

T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.5

.;.;.;N;.;.

PhyloP100

5.3

PrimateAI

Benign

0.47

PROVEAN

Benign

0.97

N;N;N;N;N;.

REVEL

Benign

0.26

Sift

Benign

1.0

T;T;T;T;T;.

Sift4G

Benign

1.0

T;T;T;T;T;.

Polyphen

0.048

.;.;.;B;.;.

Vest4

0.031

MPC

0.25

ClinPred

0.0036

GERP RS

3.9

Varity_R

0.071

gMVP

0.46

Mutation Taster

=87/13

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000030

dbscSNV1_RF

Benign

0.016

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

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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