Genetic Variant CHAT:p.Leu249Val (chr10-49622143-C-G) – ACMG Classification: Benign (-20 pts)

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.745C>G(p.Leu249Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000628 in 1,553,504 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L249L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 5 hom. )

Consequence

CHAT
NM_020549.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.08

Publications

4 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=0.01505819).

BP6

Variant 10-49622143-C-G is Benign according to our data. Variant chr10-49622143-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00357 (478/133716) while in subpopulation AFR AF = 0.0129 (463/35972). AF 95% confidence interval is 0.0119. There are 2 homozygotes in GnomAd4. There are 222 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020549.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHAT	NM_020549.5	MANE Select	c.745C>G	p.Leu249Val	missense	Exon 5 of 15	NP_065574.4
CHAT	NM_001142933.2		c.499C>G	p.Leu167Val	missense	Exon 6 of 16	NP_001136405.2
CHAT	NM_001142929.2		c.391C>G	p.Leu131Val	missense	Exon 5 of 15	NP_001136401.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHAT	ENST00000337653.7	TSL:1 MANE Select	c.745C>G	p.Leu249Val	missense	Exon 5 of 15	ENSP00000337103.2
CHAT	ENST00000395562.2	TSL:1	c.499C>G	p.Leu167Val	missense	Exon 6 of 16	ENSP00000378929.2
CHAT	ENST00000339797.5	TSL:1	c.391C>G	p.Leu131Val	missense	Exon 5 of 15	ENSP00000343486.1

Frequencies

GnomAD3 genomes

AF:

0.00357

AC:

477

AN:

133586

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000936

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000244

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000162

Gnomad OTH

AF:

0.000569

GnomAD2 exomes

AF:

0.000788

AC:

198

AN:

251414

AF XY:

0.000603

show subpopulations

Gnomad AFR exome

AF:

0.0102

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000351

AC:

498

AN:

1419788

Hom.:

Cov.:

AF XY:

0.000312

AC XY:

220

AN XY:

705994

show subpopulations

African (AFR)

AF:

0.0121

AC:

388

AN:

32164

American (AMR)

AF:

0.000807

AC:

AN:

43376

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24352

East Asian (EAS)

AF:

0.00

AC:

AN:

36544

South Asian (SAS)

AF:

0.0000466

AC:

AN:

85850

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49782

Middle Eastern (MID)

AF:

0.00127

AC:

AN:

5506

European-Non Finnish (NFE)

AF:

0.0000194

AC:

AN:

1084738

Other (OTH)

AF:

0.000748

AC:

AN:

57476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

101

134

168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00357

AC:

478

AN:

133716

Hom.:

Cov.:

AF XY:

0.00343

AC XY:

222

AN XY:

64724

show subpopulations

African (AFR)

AF:

0.0129

AC:

463

AN:

35972

American (AMR)

AF:

0.000935

AC:

AN:

12836

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3180

East Asian (EAS)

AF:

0.00

AC:

AN:

4346

South Asian (SAS)

AF:

0.000244

AC:

AN:

4098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8654

Middle Eastern (MID)

AF:

0.00

AC:

AN:

242

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

61788

Other (OTH)

AF:

0.000562

AC:

AN:

1780

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000526

Hom.:

Bravo

AF:

0.00347

ESP6500AA

AF:

0.0116

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000972

AC:

118

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial infantile myasthenia (2)

not provided (2)

CHAT-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Benign

-0.15

Eigen_PC

Benign

0.024

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.73

MetaRNN

Benign

0.015

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

1.5

PhyloP100

1.1

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.32

Sift

Benign

0.11

Sift4G

Benign

0.10

Polyphen

0.046

Vest4

0.26

MVP

0.88

MPC

0.34

ClinPred

0.010

GERP RS

4.8

Varity_R

0.40

gMVP

0.47

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over