10-49664356-C-G

Variant names:

• chr10-49664356-C-G
• rs11101202
• NM_020549.5:c.1978-421C>G

Variant summary

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

The NM_020549.5(CHAT):​c.1978-421C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 152,026 control chromosomes in the GnomAD database, including 13,326 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 0.41 (13326 hom., cov: 32)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 6 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=-0.68).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5	c.1978-421C>G		intron_variant	Intron 14 of 14	ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7	c.1978-421C>G		intron_variant	Intron 14 of 14	1	NM_020549.5	ENSP00000337103.2

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62612 AN: 151904 Hom.: 13318 Cov.: 32

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.689

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.408

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

GnomAD4 genome AF: 0.412 AC: 62653 AN: 152026 Hom.: 13326 Cov.: 32 AF XY: 0.410 AC XY: 30480 AN XY: 74322

African (AFR) AF: 0.337 AC: 13946 AN: 41440

American (AMR) AF: 0.382 AC: 5832 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 1397 AN: 3472

East Asian (EAS) AF: 0.689 AC: 3564 AN: 5170

South Asian (SAS) AF: 0.542 AC: 2609 AN: 4810

European-Finnish (FIN) AF: 0.343 AC: 3622 AN: 10556

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.447 AC: 30389 AN: 67978

Other (OTH) AF: 0.407 AC: 859 AN: 2108

Alfa AF: 0.416 Hom.: 1650

Bravo AF: 0.409

Asia WGS AF: 0.599 AC: 2086 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.61
PhyloP100		1.0
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: rs11101202; hg19: chr10-50872402;