ENST00000466590.6:n.-10T>A

Variant names:

• chr10-49614027-G-A
• rs1392580226
• ENST00000339797.5:c.-68-2475G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000466590.6(CHAT):​n.-163G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHAT ENST00000466590.6 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.46
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000466590.6. 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_020984.4		c.-68-2475G>A		intron	N/A	NP_066264.4
	CHAT	NM_020985.4		c.-240-277G>A		intron	N/A	NP_066265.4
	CHAT	NM_020986.4		c.-69+825G>A		intron	N/A	NP_066266.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	ENST00000339797.5	TSL:1	c.-68-2475G>A		intron	N/A	ENSP00000343486.1
	CHAT	ENST00000460699.5	TSL:1	n.96-277G>A		intron	N/A
	CHAT	ENST00000481336.5	TSL:1	n.84+825G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1139602 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 571334

African (AFR) AF: 0.00 AC: 0 AN: 27258

American (AMR) AF: 0.00 AC: 0 AN: 34618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22840

East Asian (EAS) AF: 0.00 AC: 0 AN: 34582

South Asian (SAS) AF: 0.00 AC: 0 AN: 70796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3550

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 862832

Other (OTH) AF: 0.00 AC: 0 AN: 49748

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.090
DANN	Benign	0.73
PhyloP100		-1.5
PromoterAI		-0.0038	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1392580226; hg19: chr10-50822073;