10-49614464-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_020549.5(CHAT):c.275C>G(p.Pro92Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000414 in 1,546,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P92Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CHAT
NM_020549.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -1.29

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04904315).

BP6

Variant 10-49614464-C-G is Benign according to our data. Variant chr10-49614464-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 582350.

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	UniProt
CHAT	NM_020549.5	MANE Select	c.275C>G	p.Pro92Arg	missense	Exon 1 of 15	NP_065574.4	P28329-1
CHAT	NM_001142933.2		c.-42C>G		5_prime_UTR	Exon 1 of 16	NP_001136405.2	P28329-2
CHAT	NM_001142929.2		c.-80C>G		5_prime_UTR	Exon 1 of 15	NP_001136401.2	P28329-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHAT	ENST00000337653.7	TSL:1 MANE Select	c.275C>G	p.Pro92Arg	missense	Exon 1 of 15	ENSP00000337103.2	P28329-1
CHAT	ENST00000395562.2	TSL:1	c.-42C>G		5_prime_UTR	Exon 1 of 16	ENSP00000378929.2	P28329-2
CHAT	ENST00000339797.5	TSL:1	c.-68-2038C>G		intron	N/A	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes

AF:

0.000211

AC:

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000141

AC:

AN:

141742

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000144

Gnomad AMR exome

AF:

0.0000408

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000229

AC:

AN:

1394568

Hom.:

Cov.:

AF XY:

0.0000174

AC XY:

AN XY:

687944

show subpopulations

African (AFR)

AF:

0.000507

AC:

AN:

31582

American (AMR)

AF:

0.0000280

AC:

AN:

35758

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25150

East Asian (EAS)

AF:

0.00

AC:

AN:

35830

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4070

European-Non Finnish (NFE)

AF:

0.0000130

AC:

AN:

1078994

Other (OTH)

AF:

0.00

AC:

AN:

57796

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000210

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.000723

AC:

AN:

41520

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

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:

0.00

Hom.:

Bravo

AF:

0.000219

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial infantile myasthenia (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.072

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0070

LIST_S2

Benign

0.23

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.049

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.55

PhyloP100

-1.3

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.27

REVEL

Benign

0.24

Sift

Uncertain

0.027

Sift4G

Uncertain

0.0070

Polyphen

0.0

Vest4

0.054

MVP

0.56

MPC

0.26

ClinPred

0.070

GERP RS

-4.2

PromoterAI

0.020

Neutral

(source)

Varity_R

0.046

gMVP

0.11

Mutation Taster

=97/3

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

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