chr10-49648597-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020549.5(CHAT):c.1372C>T(p.Leu458Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00511 in 1,611,882 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0037 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 26 hom. )

Consequence

CHAT
NM_020549.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.91

Publications

7 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=0.013102263).

BP6

Variant 10-49648597-C-T is Benign according to our data. Variant chr10-49648597-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 199158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00367 (559/152292) while in subpopulation NFE AF = 0.00523 (356/68028). AF 95% confidence interval is 0.00478. There are 3 homozygotes in GnomAd4. There are 302 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5 link	c.1372C>T	p.Leu458Phe	missense_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.1372C>T	p.Leu458Phe	missense_variant	Exon 9 of 15	1	NM_020549.5	ENSP00000337103.2		P28329-1

Frequencies

GnomAD3 genomes

AF:

0.00367

AC:

559

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0130

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00523

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00388

AC:

967

AN:

249232

AF XY:

0.00372

show subpopulations

Gnomad AFR exome

AF:

0.000808

Gnomad AMR exome

AF:

0.000958

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0150

Gnomad NFE exome

AF:

0.00505

Gnomad OTH exome

AF:

0.00477

GnomAD4 exome

AF:

0.00527

AC:

7685

AN:

1459590

Hom.:

Cov.:

AF XY:

0.00504

AC XY:

3659

AN XY:

726158

show subpopulations

African (AFR)

AF:

0.000598

AC:

AN:

33444

American (AMR)

AF:

0.000917

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.000139

AC:

AN:

86026

European-Finnish (FIN)

AF:

0.0131

AC:

696

AN:

53288

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00594

AC:

6597

AN:

1110256

Other (OTH)

AF:

0.00507

AC:

306

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

342

684

1025

1367

1709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

256

512

768

1024

1280

<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:

0.00367

AC:

559

AN:

152292

Hom.:

Cov.:

AF XY:

0.00406

AC XY:

302

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41556

American (AMR)

AF:

0.000980

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0130

AC:

138

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00523

AC:

356

AN:

68028

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

103

137

171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00474

Hom.:

Bravo

AF:

0.00271

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00365

AC:

443

EpiCase

AF:

0.00442

EpiControl

AF:

0.00541

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CHAT: BS2 -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Nov 23, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

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

Benign

0.30

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

.;.;.;T;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

.;.;D;D;D;D

MetaRNN

Benign

0.013

T;T;T;T;T;T

MetaSVM

Uncertain

0.57

MutationAssessor

Uncertain

2.4

.;.;.;M;.;.

PhyloP100

7.9

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.2

N;N;N;N;N;.

REVEL

Pathogenic

0.83

Sift

Benign

0.070

T;T;T;T;T;.

Sift4G

Benign

0.12

T;T;T;T;T;.

Polyphen

1.0

.;.;.;D;.;.

Vest4

0.77

MVP

0.97

MPC

0.93

ClinPred

0.014

GERP RS

5.0

Varity_R

0.69

gMVP

0.67

Mutation Taster

=95/5

polymorphism

(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

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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