chr10-49655997-T-A

Variant names:

• chr10-49655997-T-A
• rs6537546
• NM_020549.5:c.1839+549T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020549.5(CHAT):​c.1839+549T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.823 in 152,270 control chromosomes in the GnomAD database, including 52,365 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.82 (52365 hom., cov: 33)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.461
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.901 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	NM_020549.5	MANE Select	c.1839+549T>A		intron	N/A	NP_065574.4
	CHAT	NM_001142933.2		c.1593+549T>A		intron	N/A	NP_001136405.2
	CHAT	NM_001142929.2		c.1485+549T>A		intron	N/A	NP_001136401.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	ENST00000337653.7	TSL:1 MANE Select	c.1839+549T>A		intron	N/A	ENSP00000337103.2
	CHAT	ENST00000395562.2	TSL:1	c.1593+549T>A		intron	N/A	ENSP00000378929.2
	CHAT	ENST00000339797.5	TSL:1	c.1485+549T>A		intron	N/A	ENSP00000343486.1

Frequencies

GnomAD3 genomes AF: 0.824 AC: 125325 AN: 152152 Hom.: 52361 Cov.: 33

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.764

Gnomad ASJ AF: 0.856

Gnomad EAS AF: 0.795

Gnomad SAS AF: 0.862

Gnomad FIN AF: 0.888

Gnomad MID AF: 0.902

Gnomad NFE AF: 0.907

Gnomad OTH AF: 0.849

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.823 AC: 125365 AN: 152270 Hom.: 52365 Cov.: 33 AF XY: 0.822 AC XY: 61212 AN XY: 74458

African (AFR) AF: 0.686 AC: 28496 AN: 41544

American (AMR) AF: 0.763 AC: 11669 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.856 AC: 2973 AN: 3472

East Asian (EAS) AF: 0.795 AC: 4120 AN: 5182

South Asian (SAS) AF: 0.862 AC: 4157 AN: 4820

European-Finnish (FIN) AF: 0.888 AC: 9427 AN: 10616

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

European-Non Finnish (NFE) AF: 0.907 AC: 61720 AN: 68022

Other (OTH) AF: 0.841 AC: 1780 AN: 2116

Alfa AF: 0.860 Hom.: 6655

Bravo AF: 0.805

Asia WGS AF: 0.805 AC: 2801 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.0
DANN	Benign	0.64
PhyloP100		0.46
Mutation Taster		=100/0	polymorphism (auto)

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: rs6537546; hg19: chr10-50864043;