10-49641296-T-G

Variant names:

• chr10-49641296-T-G
• rs1917818
• NM_020549.5:c.1112-5209T>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.1112-5209T>G 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 152,160 control chromosomes in the GnomAD database, including 8,142 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 (8142 hom., cov: 33)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0450
• Publications: 2 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: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.435 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	NM_020549.5	MANE Select	c.1112-5209T>G		intron	N/A	NP_065574.4	P28329-1
	CHAT	NM_001142933.2		c.866-5209T>G		intron	N/A	NP_001136405.2	P28329-2
	CHAT	NM_001142929.2		c.758-5209T>G		intron	N/A	NP_001136401.2	P28329-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	ENST00000337653.7	TSL:1 MANE Select	c.1112-5209T>G		intron	N/A	ENSP00000337103.2	P28329-1
	CHAT	ENST00000395562.2	TSL:1	c.866-5209T>G		intron	N/A	ENSP00000378929.2	P28329-2
	CHAT	ENST00000339797.5	TSL:1	c.758-5209T>G		intron	N/A	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47640 AN: 152042 Hom.: 8144 Cov.: 33

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.350

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.450

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.347

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

GnomAD4 genome AF: 0.313 AC: 47644 AN: 152160 Hom.: 8142 Cov.: 33 AF XY: 0.309 AC XY: 22993 AN XY: 74386

African (AFR) AF: 0.185 AC: 7675 AN: 41542

American (AMR) AF: 0.350 AC: 5346 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1277 AN: 3470

East Asian (EAS) AF: 0.227 AC: 1176 AN: 5172

South Asian (SAS) AF: 0.451 AC: 2171 AN: 4818

European-Finnish (FIN) AF: 0.241 AC: 2549 AN: 10590

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.387 AC: 26288 AN: 67960

Other (OTH) AF: 0.345 AC: 729 AN: 2110

Alfa AF: 0.306 Hom.: 3808

Bravo AF: 0.309

Asia WGS AF: 0.353 AC: 1230 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.0
DANN	Benign	0.35
PhyloP100		0.045
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: rs1917818; hg19: chr10-50849342;