NM_020549.5:c.1682G>A

Variant names:

• chr10-49655142-G-A
• rs80097077
• NM_020549.5:c.1682G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020549.5(CHAT):​c.1682G>A​(p.Arg561Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0096 in 1,614,060 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (78 hom.)
• Consequence: CHAT NM_020549.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 8.02
• Publications: 7 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 -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_020549.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.025550604).
• BP6: Variant 10-49655142-G-A is Benign according to our data. Variant chr10-49655142-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00811 (1235/152238) while in subpopulation AMR AF = 0.0155 (237/15288). AF 95% confidence interval is 0.0139. There are 9 homozygotes in GnomAd4. There are 607 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD gene

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.1682G>A	p.Arg561Gln	missense	Exon 12 of 15	NP_065574.4	P28329-1
	CHAT	NM_001142933.2		c.1436G>A	p.Arg479Gln	missense	Exon 13 of 16	NP_001136405.2	P28329-2
	CHAT	NM_001142929.2		c.1328G>A	p.Arg443Gln	missense	Exon 12 of 15	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.1682G>A	p.Arg561Gln	missense	Exon 12 of 15	ENSP00000337103.2	P28329-1
	CHAT	ENST00000395562.2	TSL:1	c.1436G>A	p.Arg479Gln	missense	Exon 13 of 16	ENSP00000378929.2	P28329-2
	CHAT	ENST00000339797.5	TSL:1	c.1328G>A	p.Arg443Gln	missense	Exon 12 of 15	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes AF: 0.00812 AC: 1235 AN: 152120 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00669

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00750 AC: 1885 AN: 251288 AF XY: 0.00751

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00997

Gnomad ASJ exome AF: 0.00992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00725

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00946

GnomAD4 exome AF: 0.00976 AC: 14264 AN: 1461822 Hom.: 78 Cov.: 37 AF XY: 0.00947 AC XY: 6890 AN XY: 727224

African (AFR) AF: 0.00164 AC: 55 AN: 33480

American (AMR) AF: 0.0104 AC: 465 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00830 AC: 217 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000359 AC: 31 AN: 86256

European-Finnish (FIN) AF: 0.00826 AC: 441 AN: 53372

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5768

European-Non Finnish (NFE) AF: 0.0113 AC: 12533 AN: 1111994

Other (OTH) AF: 0.00800 AC: 483 AN: 60396

GnomAD4 genome AF: 0.00811 AC: 1235 AN: 152238 Hom.: 9 Cov.: 32 AF XY: 0.00816 AC XY: 607 AN XY: 74428

African (AFR) AF: 0.00255 AC: 106 AN: 41544

American (AMR) AF: 0.0155 AC: 237 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4812

European-Finnish (FIN) AF: 0.00669 AC: 71 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0111 AC: 754 AN: 68006

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00984 Hom.: 23

Bravo AF: 0.00802

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0102 AC: 88

ExAC AF: 0.00743 AC: 902

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0110

EpiControl AF: 0.0127

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Familial infantile myasthenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.026	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		8.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.71
Sift	Benign	0.040	D
Sift4G	Benign	0.069	T
Polyphen		1.0	D
Vest4		0.66
MVP		0.96
MPC		0.96
ClinPred		0.0077	T
GERP RS		5.4
Varity_R		0.75
gMVP		0.78
Mutation Taster		=62/38	polymorphism

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: rs80097077; hg19: chr10-50863188; COSMIC: COSV104639426;