10-49664866-C-T

Variant names:

• chr10-49664866-C-T
• rs3793801
• NM_020549.5:c.2067C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020549.5(CHAT):​c.2067C>T​(p.Ile689Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,614,196 control chromosomes in the GnomAD database, including 2,610 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I689I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (266 hom., cov: 32)
  • Exomes 𝑓: 0.015 (2344 hom.)
• Consequence: CHAT NM_020549.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.22
• Publications: 12 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 -16 ACMG points.

• BP6: Variant 10-49664866-C-T is Benign according to our data. Variant chr10-49664866-C-T is described in ClinVar as Benign. ClinVar VariationId is 128722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.292 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.2067C>T	p.Ile689Ile	synonymous	Exon 15 of 15	NP_065574.4
	CHAT	NM_001142933.2		c.1821C>T	p.Ile607Ile	synonymous	Exon 16 of 16	NP_001136405.2
	CHAT	NM_001142929.2		c.1713C>T	p.Ile571Ile	synonymous	Exon 15 of 15	NP_001136401.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	ENST00000337653.7	TSL:1 MANE Select	c.2067C>T	p.Ile689Ile	synonymous	Exon 15 of 15	ENSP00000337103.2
	CHAT	ENST00000395562.2	TSL:1	c.1821C>T	p.Ile607Ile	synonymous	Exon 16 of 16	ENSP00000378929.2
	CHAT	ENST00000339797.5	TSL:1	c.1713C>T	p.Ile571Ile	synonymous	Exon 15 of 15	ENSP00000343486.1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2344 AN: 152188 Hom.: 268 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.0587

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0325 AC: 8179 AN: 251496 AF XY: 0.0328

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00863

Gnomad EAS exome AF: 0.307

Gnomad FIN exome AF: 0.0137

Gnomad NFE exome AF: 0.00214

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0145 AC: 21210 AN: 1461890 Hom.: 2344 Cov.: 32 AF XY: 0.0155 AC XY: 11298 AN XY: 727248

African (AFR) AF: 0.00111 AC: 37 AN: 33480

American (AMR) AF: 0.00190 AC: 85 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00892 AC: 233 AN: 26134

East Asian (EAS) AF: 0.325 AC: 12886 AN: 39700

South Asian (SAS) AF: 0.0529 AC: 4560 AN: 86256

European-Finnish (FIN) AF: 0.0127 AC: 681 AN: 53420

Middle Eastern (MID) AF: 0.0102 AC: 59 AN: 5768

European-Non Finnish (NFE) AF: 0.00123 AC: 1373 AN: 1112012

Other (OTH) AF: 0.0215 AC: 1296 AN: 60396

GnomAD4 genome AF: 0.0154 AC: 2339 AN: 152306 Hom.: 266 Cov.: 32 AF XY: 0.0182 AC XY: 1357 AN XY: 74466

African (AFR) AF: 0.00221 AC: 92 AN: 41578

American (AMR) AF: 0.00274 AC: 42 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3470

East Asian (EAS) AF: 0.304 AC: 1575 AN: 5174

South Asian (SAS) AF: 0.0582 AC: 280 AN: 4814

European-Finnish (FIN) AF: 0.0135 AC: 143 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00198 AC: 135 AN: 68026

Other (OTH) AF: 0.0147 AC: 31 AN: 2116

Alfa AF: 0.00677 Hom.: 282

Bravo AF: 0.0150

Asia WGS AF: 0.149 AC: 516 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Familial infantile myasthenia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	15
DANN	Benign	0.75
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: 18

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

Other links and lift over

dbSNP: rs3793801; hg19: chr10-50872912; COSMIC: COSV60321243;