chr10-49627830-G-A

Variant names:

• chr10-49627830-G-A
• rs58788269
• NM_020549.5:c.1111+45G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020549.5(CHAT):​c.1111+45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00832 in 1,593,994 control chromosomes in the GnomAD database, including 849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (462 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (387 hom.)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.379
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 10-49627830-G-A is Benign according to our data. Variant chr10-49627830-G-A is described in ClinVar as Benign. ClinVar VariationId is 261326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	NM_020549.5	MANE Select	c.1111+45G>A		intron	N/A	NP_065574.4
	CHAT	NM_001142933.2		c.865+45G>A		intron	N/A	NP_001136405.2
	CHAT	NM_001142929.2		c.757+45G>A		intron	N/A	NP_001136401.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	ENST00000337653.7	TSL:1 MANE Select	c.1111+45G>A		intron	N/A	ENSP00000337103.2
	CHAT	ENST00000395562.2	TSL:1	c.865+45G>A		intron	N/A	ENSP00000378929.2
	CHAT	ENST00000339797.5	TSL:1	c.757+45G>A		intron	N/A	ENSP00000343486.1

Frequencies

GnomAD3 genomes AF: 0.0419 AC: 6371 AN: 152094 Hom.: 462 Cov.: 33

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.0379

GnomAD2 exomes AF: 0.0117 AC: 2609 AN: 223364 AF XY: 0.00787

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.00803

Gnomad ASJ exome AF: 0.00123

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000670

Gnomad NFE exome AF: 0.000992

Gnomad OTH exome AF: 0.00844

GnomAD4 exome AF: 0.00477 AC: 6879 AN: 1441782 Hom.: 387 Cov.: 30 AF XY: 0.00406 AC XY: 2911 AN XY: 717088

African (AFR) AF: 0.147 AC: 4863 AN: 33162

American (AMR) AF: 0.00943 AC: 408 AN: 43278

Ashkenazi Jewish (ASJ) AF: 0.000963 AC: 25 AN: 25954

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39232

South Asian (SAS) AF: 0.000953 AC: 81 AN: 85020

European-Finnish (FIN) AF: 0.0000215 AC: 1 AN: 46480

Middle Eastern (MID) AF: 0.0108 AC: 51 AN: 4722

European-Non Finnish (NFE) AF: 0.000683 AC: 754 AN: 1104152

Other (OTH) AF: 0.0116 AC: 695 AN: 59782

GnomAD4 genome AF: 0.0419 AC: 6384 AN: 152212 Hom.: 462 Cov.: 33 AF XY: 0.0399 AC XY: 2971 AN XY: 74426

African (AFR) AF: 0.144 AC: 5965 AN: 41522

American (AMR) AF: 0.0171 AC: 262 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000912 AC: 62 AN: 68016

Other (OTH) AF: 0.0375 AC: 79 AN: 2108

Alfa AF: 0.0346 Hom.: 61

Bravo AF: 0.0481

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.8
DANN	Benign	0.74
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs58788269; hg19: chr10-50835876;