ENST00000395562.2:c.19G>A

Variant names:

Variant summary

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

The ENST00000395562.2(CHAT):c.19G>A(p.Asp7Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,612,640 control chromosomes in the GnomAD database, including 47,820 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 3033 hom., cov: 34)

Exomes 𝑓: 0.24 ( 44787 hom. )

Consequence

CHAT
ENST00000395562.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.43

Publications

50 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: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
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=0.0045491755).

BP6

Variant 10-49616071-G-A is Benign according to our data. Variant chr10-49616071-G-A is described in ClinVar as Benign. ClinVar VariationId is 402536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000395562.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHAT	NM_020549.5	MANE Select	c.287-431G>A		intron	N/A	NP_065574.4	P28329-1
CHAT	NM_001142933.2		c.19G>A	p.Asp7Asn	missense	Exon 2 of 16	NP_001136405.2	P28329-2
CHAT	NM_001142934.2		c.-90G>A		5_prime_UTR	Exon 2 of 16	NP_001136406.2	P28329-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHAT	ENST00000395562.2	TSL:1	c.19G>A	p.Asp7Asn	missense	Exon 2 of 16	ENSP00000378929.2	P28329-2
CHAT	ENST00000337653.7	TSL:1 MANE Select	c.287-431G>A		intron	N/A	ENSP00000337103.2	P28329-1
CHAT	ENST00000339797.5	TSL:1	c.-68-431G>A		intron	N/A	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27293

AN:

152130

Hom.:

3036

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0482

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.184

Gnomad ASJ

AF:

0.234

Gnomad EAS

AF:

0.159

Gnomad SAS

AF:

0.273

Gnomad FIN

AF:

0.181

Gnomad MID

AF:

0.213

Gnomad NFE

AF:

0.248

Gnomad OTH

AF:

0.192

GnomAD2 exomes

AF:

0.210

AC:

52261

AN:

248860

AF XY:

0.220

show subpopulations

Gnomad AFR exome

AF:

0.0416

Gnomad AMR exome

AF:

0.144

Gnomad ASJ exome

AF:

0.244

Gnomad EAS exome

AF:

0.147

Gnomad FIN exome

AF:

0.180

Gnomad NFE exome

AF:

0.247

Gnomad OTH exome

AF:

0.230

GnomAD4 exome

AF:

0.243

AC:

354404

AN:

1460392

Hom.:

44787

Cov.:

AF XY:

0.245

AC XY:

177869

AN XY:

726552

show subpopulations

African (AFR)

AF:

0.0393

AC:

1314

AN:

33466

American (AMR)

AF:

0.149

AC:

6669

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.246

AC:

6425

AN:

26128

East Asian (EAS)

AF:

0.174

AC:

6888

AN:

39694

South Asian (SAS)

AF:

0.276

AC:

23827

AN:

86226

European-Finnish (FIN)

AF:

0.186

AC:

9938

AN:

53396

Middle Eastern (MID)

AF:

0.279

AC:

1608

AN:

5764

European-Non Finnish (NFE)

AF:

0.255

AC:

283574

AN:

1110662

Other (OTH)

AF:

0.235

AC:

14161

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

13307

26614

39921

53228

66535

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9522

19044

28566

38088

47610

<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:

0.179

AC:

27284

AN:

152248

Hom.:

3033

Cov.:

AF XY:

0.179

AC XY:

13325

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0481

AC:

2000

AN:

41580

American (AMR)

AF:

0.184

AC:

2817

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.234

AC:

813

AN:

3472

East Asian (EAS)

AF:

0.158

AC:

819

AN:

5170

South Asian (SAS)

AF:

0.273

AC:

1314

AN:

4822

European-Finnish (FIN)

AF:

0.181

AC:

1923

AN:

10598

Middle Eastern (MID)

AF:

0.212

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.248

AC:

16889

AN:

67988

Other (OTH)

AF:

0.191

AC:

403

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1142

2284

3427

4569

5711

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

308

616

924

1232

1540

<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:

0.228

Hom.:

16365

Bravo

AF:

0.170

TwinsUK

AF:

0.257

AC:

953

ALSPAC

AF:

0.272

AC:

1049

ESP6500AA

AF:

0.0501

AC:

157

ESP6500EA

AF:

0.248

AC:

1775

ExAC

AF:

0.211

AC:

25417

Asia WGS

AF:

0.191

AC:

663

AN:

3478

EpiCase

AF:

0.261

EpiControl

AF:

0.259

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Familial infantile myasthenia (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

7.6

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.1

PhyloP100

1.4

PROVEAN

Benign

0.13

REVEL

Benign

0.17

Sift

Pathogenic

0.0

Sift4G

Benign

0.81

Vest4

0.051

ClinPred

0.029

GERP RS

3.2

Mutation Taster

=100/0

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

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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