dbSNP rs4838537: CHAT:c.388-50C>T (chr10-49619675-C-T) – ACMG Classification: Benign (-20 pts)

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.388-50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0515 in 1,569,936 control chromosomes in the GnomAD database, including 5,683 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.068 ( 748 hom., cov: 32)

Exomes 𝑓: 0.050 ( 4935 hom. )

Consequence

CHAT
NM_020549.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.293

Publications

3 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 (BayesDel_noAF=-0.81).

BP6

Variant 10-49619675-C-T is Benign according to our data. Variant chr10-49619675-C-T is described in ClinVar as Benign. ClinVar VariationId is 261335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
CHAT	NM_020549.5	MANE Select	c.388-50C>T	intron	N/A	NP_065574.4	P28329-1
CHAT	NM_001142933.2		c.142-50C>T	intron	N/A	NP_001136405.2	P28329-2
CHAT	NM_001142929.2		c.34-50C>T	intron	N/A	NP_001136401.2	P28329-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHAT	ENST00000337653.7	TSL:1 MANE Select	c.388-50C>T	intron	N/A	ENSP00000337103.2	P28329-1
CHAT	ENST00000395562.2	TSL:1	c.142-50C>T	intron	N/A	ENSP00000378929.2	P28329-2
CHAT	ENST00000339797.5	TSL:1	c.34-50C>T	intron	N/A	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes

AF:

0.0680

AC:

10336

AN:

152102

Hom.:

729

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0644

Gnomad AMI

AF:

0.00661

Gnomad AMR

AF:

0.231

Gnomad ASJ

AF:

0.0377

Gnomad EAS

AF:

0.216

Gnomad SAS

AF:

0.0830

Gnomad FIN

AF:

0.0314

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0293

Gnomad OTH

AF:

0.0755

GnomAD2 exomes

AF:

0.102

AC:

23667

AN:

231130

AF XY:

0.0914

show subpopulations

Gnomad AFR exome

AF:

0.0652

Gnomad AMR exome

AF:

0.354

Gnomad ASJ exome

AF:

0.0398

Gnomad EAS exome

AF:

0.224

Gnomad FIN exome

AF:

0.0325

Gnomad NFE exome

AF:

0.0303

Gnomad OTH exome

AF:

0.0811

GnomAD4 exome

AF:

0.0497

AC:

70489

AN:

1417716

Hom.:

4935

Cov.:

AF XY:

0.0490

AC XY:

34631

AN XY:

707044

show subpopulations

African (AFR)

AF:

0.0650

AC:

2134

AN:

32822

American (AMR)

AF:

0.341

AC:

14968

AN:

43920

Ashkenazi Jewish (ASJ)

AF:

0.0407

AC:

1052

AN:

25826

East Asian (EAS)

AF:

0.225

AC:

8885

AN:

39470

South Asian (SAS)

AF:

0.0787

AC:

6651

AN:

84492

European-Finnish (FIN)

AF:

0.0340

AC:

1414

AN:

41580

Middle Eastern (MID)

AF:

0.0459

AC:

188

AN:

4100

European-Non Finnish (NFE)

AF:

0.0290

AC:

31533

AN:

1086410

Other (OTH)

AF:

0.0620

AC:

3664

AN:

59096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

3506

7011

10517

14022

17528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1502

3004

4506

6008

7510

<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:

0.0681

AC:

10373

AN:

152220

Hom.:

748

Cov.:

AF XY:

0.0725

AC XY:

5397

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0643

AC:

2670

AN:

41538

American (AMR)

AF:

0.232

AC:

3545

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0377

AC:

131

AN:

3472

East Asian (EAS)

AF:

0.216

AC:

1119

AN:

5172

South Asian (SAS)

AF:

0.0824

AC:

397

AN:

4818

European-Finnish (FIN)

AF:

0.0314

AC:

333

AN:

10602

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0293

AC:

1990

AN:

68016

Other (OTH)

AF:

0.0833

AC:

176

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

434

868

1302

1736

2170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<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:

0.0482

Hom.:

173

Bravo

AF:

0.0885

Asia WGS

AF:

0.178

AC:

618

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.2

(source)

DANN

Benign

0.78

PhyloP100

-0.29

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