Genetic Variant NM_020549.5:c.909C>T (chr10-49625629-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_020549.5(CHAT):c.909C>T(p.His303His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000541 in 1,581,602 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00046 ( 1 hom. )

Consequence

CHAT
NM_020549.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0300

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: 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 10-49625629-C-T is Benign according to our data. Variant chr10-49625629-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 497741.

BP7

Synonymous conserved (PhyloP=-0.03 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00127 (194/152334) while in subpopulation AMR AF = 0.00274 (42/15306). AF 95% confidence interval is 0.00224. There are 0 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.909C>T	p.His303His	synonymous	Exon 6 of 15	NP_065574.4
CHAT	NM_001142933.2		c.663C>T	p.His221His	synonymous	Exon 7 of 16	NP_001136405.2
CHAT	NM_001142929.2		c.555C>T	p.His185His	synonymous	Exon 6 of 15	NP_001136401.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHAT	ENST00000337653.7	TSL:1 MANE Select	c.909C>T	p.His303His	synonymous	Exon 6 of 15	ENSP00000337103.2
CHAT	ENST00000395562.2	TSL:1	c.663C>T	p.His221His	synonymous	Exon 7 of 16	ENSP00000378929.2
CHAT	ENST00000339797.5	TSL:1	c.555C>T	p.His185His	synonymous	Exon 6 of 15	ENSP00000343486.1

Frequencies

GnomAD3 genomes

AF:

0.00127

AC:

193

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.000730

AC:

143

AN:

195844

AF XY:

0.000747

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.00174

Gnomad ASJ exome

AF:

0.00442

Gnomad EAS exome

AF:

0.0000682

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000252

Gnomad OTH exome

AF:

0.00136

GnomAD4 exome

AF:

0.000463

AC:

662

AN:

1429268

Hom.:

Cov.:

AF XY:

0.000465

AC XY:

329

AN XY:

707788

show subpopulations

African (AFR)

AF:

0.00286

AC:

AN:

32822

American (AMR)

AF:

0.00196

AC:

AN:

39696

Ashkenazi Jewish (ASJ)

AF:

0.00392

AC:

100

AN:

25492

East Asian (EAS)

AF:

0.0000262

AC:

AN:

38240

South Asian (SAS)

AF:

0.0000122

AC:

AN:

82100

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51168

Middle Eastern (MID)

AF:

0.00227

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.000289

AC:

316

AN:

1094810

Other (OTH)

AF:

0.000997

AC:

AN:

59204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

126

168

210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.00127

AC:

194

AN:

152334

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

102

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00265

AC:

110

AN:

41582

American (AMR)

AF:

0.00274

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68024

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.000950

Hom.:

Bravo

AF:

0.00174

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Familial infantile myasthenia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

1.3

(source)

DANN

Benign

0.56

PhyloP100

-0.030

Mutation Taster

=96/4

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