rs12257601

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.753-26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,610,322 control chromosomes in the GnomAD database, including 3,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.086 ( 1883 hom., cov: 33)

Exomes 𝑓: 0.0094 ( 1681 hom. )

Consequence

CHAT
NM_020549.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.37

Publications

1 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

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 10-49625447-C-T is Benign according to our data. Variant chr10-49625447-C-T is described in ClinVar as Benign. ClinVar VariationId is 261338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 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.753-26C>T	intron	N/A	NP_065574.4	P28329-1
CHAT	NM_001142933.2		c.507-26C>T	intron	N/A	NP_001136405.2	P28329-2
CHAT	NM_001142929.2		c.399-26C>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.753-26C>T	intron	N/A	ENSP00000337103.2	P28329-1
CHAT	ENST00000395562.2	TSL:1	c.507-26C>T	intron	N/A	ENSP00000378929.2	P28329-2
CHAT	ENST00000339797.5	TSL:1	c.399-26C>T	intron	N/A	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes

AF:

0.0860

AC:

13086

AN:

152126

Hom.:

1861

Cov.:

show subpopulations

Gnomad AFR

AF:

0.296

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0363

Gnomad ASJ

AF:

0.0204

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000985

Gnomad OTH

AF:

0.0616

GnomAD2 exomes

AF:

0.0231

AC:

5753

AN:

248606

AF XY:

0.0173

show subpopulations

Gnomad AFR exome

AF:

0.303

Gnomad AMR exome

AF:

0.0150

Gnomad ASJ exome

AF:

0.0195

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000962

Gnomad OTH exome

AF:

0.0119

GnomAD4 exome

AF:

0.00937

AC:

13662

AN:

1458078

Hom.:

1681

Cov.:

AF XY:

0.00809

AC XY:

5866

AN XY:

725312

show subpopulations

African (AFR)

AF:

0.310

AC:

10317

AN:

33334

American (AMR)

AF:

0.0169

AC:

756

AN:

44610

Ashkenazi Jewish (ASJ)

AF:

0.0182

AC:

475

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.000733

AC:

AN:

85906

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53192

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

4172

European-Non Finnish (NFE)

AF:

0.000624

AC:

693

AN:

1110918

Other (OTH)

AF:

0.0214

AC:

1288

AN:

60150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

511

1022

1533

2044

2555

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.0864

AC:

13153

AN:

152244

Hom.:

1883

Cov.:

AF XY:

0.0838

AC XY:

6239

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.297

AC:

12323

AN:

41496

American (AMR)

AF:

0.0363

AC:

555

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0204

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000985

AC:

AN:

68022

Other (OTH)

AF:

0.0610

AC:

129

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

488

975

1463

1950

2438

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

252

378

504

630

<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:

0.0390

Hom.:

133

Bravo

AF:

0.0993

Asia WGS

AF:

0.0210

AC:

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

-0.70

CADD

Benign

7.0

(source)

DANN

Benign

0.83

PhyloP100

1.4

La Branchor

0.74

BranchPoint Hunter

3.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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