NM_020549.5:c.1111+7898G>A

Variant names:

• chr10-49635683-G-A
• rs2177369
• NM_020549.5:c.1111+7898G>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.1111+7898G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 151,970 control chromosomes in the GnomAD database, including 8,121 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 0.31 (8121 hom., cov: 32)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.232
• Publications: 12 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=-0.7).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5	c.1111+7898G>A		intron_variant	Intron 7 of 14	ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7	c.1111+7898G>A		intron_variant	Intron 7 of 14	1	NM_020549.5	ENSP00000337103.2

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47546 AN: 151850 Hom.: 8123 Cov.: 32

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.350

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.348

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

GnomAD4 genome AF: 0.313 AC: 47551 AN: 151970 Hom.: 8121 Cov.: 32 AF XY: 0.309 AC XY: 22947 AN XY: 74280

African (AFR) AF: 0.185 AC: 7668 AN: 41460

American (AMR) AF: 0.350 AC: 5339 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1263 AN: 3464

East Asian (EAS) AF: 0.227 AC: 1172 AN: 5166

South Asian (SAS) AF: 0.447 AC: 2156 AN: 4822

European-Finnish (FIN) AF: 0.241 AC: 2538 AN: 10540

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.386 AC: 26254 AN: 67944

Other (OTH) AF: 0.346 AC: 731 AN: 2112

Alfa AF: 0.354 Hom.: 13540

Bravo AF: 0.308

Asia WGS AF: 0.349 AC: 1214 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.8
DANN	Benign	0.86
PhyloP100		0.23
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: rs2177369; hg19: chr10-50843729;