10-49655101-T-C

Variant names:

• chr10-49655101-T-C
• rs8178992
• NM_020549.5:c.1641T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020549.5(CHAT):​c.1641T>C​(p.His547His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.882 in 1,613,882 control chromosomes in the GnomAD database, including 630,914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (52514 hom., cov: 32)
  • Exomes 𝑓: 0.89 (578400 hom.)
• Consequence: CHAT NM_020549.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.150
• Publications: 24 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-49655101-T-C is Benign according to our data. Variant chr10-49655101-T-C is described in ClinVar as Benign. ClinVar VariationId is 128719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.901 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5	c.1641T>C	p.His547His	synonymous_variant	Exon 12 of 15	ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7	c.1641T>C	p.His547His	synonymous_variant	Exon 12 of 15	1	NM_020549.5	ENSP00000337103.2

Frequencies

GnomAD3 genomes AF: 0.825 AC: 125481 AN: 152022 Hom.: 52510 Cov.: 32

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.765

Gnomad ASJ AF: 0.856

Gnomad EAS AF: 0.795

Gnomad SAS AF: 0.862

Gnomad FIN AF: 0.893

Gnomad MID AF: 0.902

Gnomad NFE AF: 0.907

Gnomad OTH AF: 0.848

GnomAD2 exomes AF: 0.844 AC: 212168 AN: 251374 AF XY: 0.854

Gnomad AFR exome AF: 0.686

Gnomad AMR exome AF: 0.679

Gnomad ASJ exome AF: 0.858

Gnomad EAS exome AF: 0.803

Gnomad FIN exome AF: 0.890

Gnomad NFE exome AF: 0.907

Gnomad OTH exome AF: 0.861

GnomAD4 exome AF: 0.888 AC: 1297416 AN: 1461742 Hom.: 578400 Cov.: 54 AF XY: 0.888 AC XY: 645965 AN XY: 727188

African (AFR) AF: 0.677 AC: 22672 AN: 33466

American (AMR) AF: 0.686 AC: 30696 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.854 AC: 22319 AN: 26136

East Asian (EAS) AF: 0.785 AC: 31164 AN: 39700

South Asian (SAS) AF: 0.866 AC: 74717 AN: 86254

European-Finnish (FIN) AF: 0.891 AC: 47554 AN: 53394

Middle Eastern (MID) AF: 0.865 AC: 4987 AN: 5768

European-Non Finnish (NFE) AF: 0.909 AC: 1010528 AN: 1111906

Other (OTH) AF: 0.874 AC: 52779 AN: 60394

GnomAD4 genome AF: 0.825 AC: 125521 AN: 152140 Hom.: 52514 Cov.: 32 AF XY: 0.824 AC XY: 61278 AN XY: 74368

African (AFR) AF: 0.690 AC: 28623 AN: 41468

American (AMR) AF: 0.765 AC: 11694 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.856 AC: 2971 AN: 3470

East Asian (EAS) AF: 0.795 AC: 4113 AN: 5174

South Asian (SAS) AF: 0.862 AC: 4147 AN: 4810

European-Finnish (FIN) AF: 0.893 AC: 9466 AN: 10604

Middle Eastern (MID) AF: 0.891 AC: 262 AN: 294

European-Non Finnish (NFE) AF: 0.907 AC: 61706 AN: 68000

Other (OTH) AF: 0.841 AC: 1778 AN: 2114

Alfa AF: 0.878 Hom.: 266055

Bravo AF: 0.807

Asia WGS AF: 0.804 AC: 2798 AN: 3478

EpiCase AF: 0.905

EpiControl AF: 0.906

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Nov 17, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial infantile myasthenia Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 11, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.97
DANN	Benign	0.40
PhyloP100		-0.15
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs8178992; hg19: chr10-50863147; COSMIC: COSV60329737;