NM_020549.5:c.388-50C>T

Variant names:

• chr10-49619675-C-T
• rs4838537
• NM_020549.5:c.388-50C>T

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.388-50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0515 in 1,569,936 control chromosomes in the GnomAD database, including 5,683 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (748 hom., cov: 32)
  • Exomes 𝑓: 0.050 (4935 hom.)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.293
• Publications: 3 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: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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=-0.81).
• BP6: Variant 10-49619675-C-T is Benign according to our data. Variant chr10-49619675-C-T is described in ClinVar as Benign. ClinVar VariationId is 261335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.226 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.388-50C>T		intron	N/A	NP_065574.4	P28329-1
	CHAT	NM_001142933.2		c.142-50C>T		intron	N/A	NP_001136405.2	P28329-2
	CHAT	NM_001142929.2		c.34-50C>T		intron	N/A	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.388-50C>T		intron	N/A	ENSP00000337103.2	P28329-1
	CHAT	ENST00000395562.2	TSL:1	c.142-50C>T		intron	N/A	ENSP00000378929.2	P28329-2
	CHAT	ENST00000339797.5	TSL:1	c.34-50C>T		intron	N/A	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes AF: 0.0680 AC: 10336 AN: 152102 Hom.: 729 Cov.: 32

Gnomad AFR AF: 0.0644

Gnomad AMI AF: 0.00661

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.0377

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.0830

Gnomad FIN AF: 0.0314

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0293

Gnomad OTH AF: 0.0755

GnomAD2 exomes AF: 0.102 AC: 23667 AN: 231130 AF XY: 0.0914

Gnomad AFR exome AF: 0.0652

Gnomad AMR exome AF: 0.354

Gnomad ASJ exome AF: 0.0398

Gnomad EAS exome AF: 0.224

Gnomad FIN exome AF: 0.0325

Gnomad NFE exome AF: 0.0303

Gnomad OTH exome AF: 0.0811

GnomAD4 exome AF: 0.0497 AC: 70489 AN: 1417716 Hom.: 4935 Cov.: 28 AF XY: 0.0490 AC XY: 34631 AN XY: 707044

African (AFR) AF: 0.0650 AC: 2134 AN: 32822

American (AMR) AF: 0.341 AC: 14968 AN: 43920

Ashkenazi Jewish (ASJ) AF: 0.0407 AC: 1052 AN: 25826

East Asian (EAS) AF: 0.225 AC: 8885 AN: 39470

South Asian (SAS) AF: 0.0787 AC: 6651 AN: 84492

European-Finnish (FIN) AF: 0.0340 AC: 1414 AN: 41580

Middle Eastern (MID) AF: 0.0459 AC: 188 AN: 4100

European-Non Finnish (NFE) AF: 0.0290 AC: 31533 AN: 1086410

Other (OTH) AF: 0.0620 AC: 3664 AN: 59096

GnomAD4 genome AF: 0.0681 AC: 10373 AN: 152220 Hom.: 748 Cov.: 32 AF XY: 0.0725 AC XY: 5397 AN XY: 74420

African (AFR) AF: 0.0643 AC: 2670 AN: 41538

American (AMR) AF: 0.232 AC: 3545 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0377 AC: 131 AN: 3472

East Asian (EAS) AF: 0.216 AC: 1119 AN: 5172

South Asian (SAS) AF: 0.0824 AC: 397 AN: 4818

European-Finnish (FIN) AF: 0.0314 AC: 333 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0293 AC: 1990 AN: 68016

Other (OTH) AF: 0.0833 AC: 176 AN: 2114

Alfa AF: 0.0482 Hom.: 173

Bravo AF: 0.0885

Asia WGS AF: 0.178 AC: 618 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	-0.81
CADD	Benign	2.2
DANN	Benign	0.78
PhyloP100		-0.29
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: rs4838537; hg19: chr10-50827721; COSMIC: COSV60323727;