10-49655101-T-C

Position:

• chr10-49655101-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020549.5(CHAT):​c.1641T>C​(p.His547=) 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:10
• Conservation: PhyloP100: -0.150

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 128719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49655101-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
CHAT	NM_020549.5	c.1641T>C	p.His547=	synonymous_variant	12/15	ENST00000337653.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHAT	ENST00000337653.7	c.1641T>C	p.His547=	synonymous_variant	12/15	1	NM_020549.5	P2

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

GnomAD3 exomes AF: 0.844 AC: 212168 AN: 251374 Hom.: 90623 AF XY: 0.854 AC XY: 116123 AN XY: 135898

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 SAS exome AF: 0.866

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

Gnomad4 AFR exome AF: 0.677

Gnomad4 AMR exome AF: 0.686

Gnomad4 ASJ exome AF: 0.854

Gnomad4 EAS exome AF: 0.785

Gnomad4 SAS exome AF: 0.866

Gnomad4 FIN exome AF: 0.891

Gnomad4 NFE exome AF: 0.909

Gnomad4 OTH exome AF: 0.874

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

Gnomad4 AFR AF: 0.690

Gnomad4 AMR AF: 0.765

Gnomad4 ASJ AF: 0.856

Gnomad4 EAS AF: 0.795

Gnomad4 SAS AF: 0.862

Gnomad4 FIN AF: 0.893

Gnomad4 NFE AF: 0.907

Gnomad4 OTH AF: 0.841

Alfa AF: 0.887 Hom.: 139236

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 17, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2016	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. -

Familial infantile myasthenia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 11, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.97
DANN	Benign	0.40

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

LitVar

Other links and lift over

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