10-49639951-C-T

Variant names:

• chr10-49639951-C-T
• rs12266458
• NM_020549.5:c.1112-6554C>T

Variant summary

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

The NM_020549.5(CHAT):​c.1112-6554C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 152,136 control chromosomes in the GnomAD database, including 1,458 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 0.12 (1458 hom., cov: 32)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.665
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.422 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.1112-6554C>T		intron	N/A	NP_065574.4	P28329-1
	CHAT	NM_001142933.2		c.866-6554C>T		intron	N/A	NP_001136405.2	P28329-2
	CHAT	NM_001142929.2		c.758-6554C>T		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.1112-6554C>T		intron	N/A	ENSP00000337103.2	P28329-1
	CHAT	ENST00000395562.2	TSL:1	c.866-6554C>T		intron	N/A	ENSP00000378929.2	P28329-2
	CHAT	ENST00000339797.5	TSL:1	c.758-6554C>T		intron	N/A	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17677 AN: 152020 Hom.: 1444 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0761

Gnomad OTH AF: 0.105

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

GnomAD4 genome AF: 0.117 AC: 17735 AN: 152136 Hom.: 1458 Cov.: 32 AF XY: 0.123 AC XY: 9139 AN XY: 74386

African (AFR) AF: 0.118 AC: 4896 AN: 41526

American (AMR) AF: 0.146 AC: 2226 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 393 AN: 3472

East Asian (EAS) AF: 0.437 AC: 2257 AN: 5168

South Asian (SAS) AF: 0.193 AC: 926 AN: 4810

European-Finnish (FIN) AF: 0.143 AC: 1512 AN: 10594

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0761 AC: 5175 AN: 67974

Other (OTH) AF: 0.113 AC: 238 AN: 2110

Alfa AF: 0.102 Hom.: 273

Bravo AF: 0.119

Asia WGS AF: 0.284 AC: 984 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.45
DANN	Benign	0.53
PhyloP100		-0.67
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: rs12266458; hg19: chr10-50847997;