NM_020549.5:c.1122C>T

Variant names:

• chr10-49646515-C-T
• rs61115650
• NM_020549.5:c.1122C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020549.5(CHAT):​c.1122C>T​(p.Asn374Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00364 in 1,614,170 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (94 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (89 hom.)
• Consequence: CHAT NM_020549.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.43
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 10-49646515-C-T is Benign according to our data. Variant chr10-49646515-C-T is described in ClinVar as Benign. ClinVar VariationId is 128715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0622 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.1122C>T	p.Asn374Asn	synonymous	Exon 8 of 15	NP_065574.4	P28329-1
	CHAT	NM_001142933.2		c.876C>T	p.Asn292Asn	synonymous	Exon 9 of 16	NP_001136405.2	P28329-2
	CHAT	NM_001142929.2		c.768C>T	p.Asn256Asn	synonymous	Exon 8 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.1122C>T	p.Asn374Asn	synonymous	Exon 8 of 15	ENSP00000337103.2	P28329-1
	CHAT	ENST00000395562.2	TSL:1	c.876C>T	p.Asn292Asn	synonymous	Exon 9 of 16	ENSP00000378929.2	P28329-2
	CHAT	ENST00000339797.5	TSL:1	c.768C>T	p.Asn256Asn	synonymous	Exon 8 of 15	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2859 AN: 152200 Hom.: 94 Cov.: 33

Gnomad AFR AF: 0.0643

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00948

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00506 AC: 1271 AN: 251288 AF XY: 0.00361

Gnomad AFR exome AF: 0.0668

Gnomad AMR exome AF: 0.00396

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00207 AC: 3019 AN: 1461852 Hom.: 89 Cov.: 32 AF XY: 0.00179 AC XY: 1300 AN XY: 727234

African (AFR) AF: 0.0671 AC: 2246 AN: 33466

American (AMR) AF: 0.00445 AC: 199 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.000232 AC: 258 AN: 1112010

Other (OTH) AF: 0.00495 AC: 299 AN: 60392

GnomAD4 genome AF: 0.0188 AC: 2863 AN: 152318 Hom.: 94 Cov.: 33 AF XY: 0.0181 AC XY: 1345 AN XY: 74476

African (AFR) AF: 0.0642 AC: 2667 AN: 41552

American (AMR) AF: 0.00947 AC: 145 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68028

Other (OTH) AF: 0.0151 AC: 32 AN: 2116

Alfa AF: 0.00885 Hom.: 18

Bravo AF: 0.0219

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Familial infantile myasthenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.4
DANN	Benign	0.88
PhyloP100		1.4
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: rs61115650; hg19: chr10-50854561;