chr10-49646721-G-A

Variant names:

• chr10-49646721-G-A
• rs11101192
• NM_020549.5:c.1281+47G>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.1281+47G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,600,960 control chromosomes in the GnomAD database, including 2,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (276 hom., cov: 33)
  • Exomes 𝑓: 0.016 (1913 hom.)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.24
• Publications: 0 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=-0.9).
• BP6: Variant 10-49646721-G-A is Benign according to our data. Variant chr10-49646721-G-A is described in ClinVar as Benign. ClinVar VariationId is 261329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.225 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.1281+47G>A		intron	N/A	NP_065574.4
	CHAT	NM_001142933.2		c.1035+47G>A		intron	N/A	NP_001136405.2
	CHAT	NM_001142929.2		c.927+47G>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.1281+47G>A		intron	N/A	ENSP00000337103.2
	CHAT	ENST00000395562.2	TSL:1	c.1035+47G>A		intron	N/A	ENSP00000378929.2
	CHAT	ENST00000339797.5	TSL:1	c.927+47G>A		intron	N/A	ENSP00000343486.1

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4357 AN: 152202 Hom.: 276 Cov.: 33

Gnomad AFR AF: 0.0297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0987

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.0453

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0550 AC: 12795 AN: 232518 AF XY: 0.0481

Gnomad AFR exome AF: 0.0327

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.00710

Gnomad EAS exome AF: 0.254

Gnomad FIN exome AF: 0.00265

Gnomad NFE exome AF: 0.000824

Gnomad OTH exome AF: 0.0313

GnomAD4 exome AF: 0.0162 AC: 23482 AN: 1448642 Hom.: 1913 Cov.: 30 AF XY: 0.0161 AC XY: 11565 AN XY: 720548

African (AFR) AF: 0.0300 AC: 993 AN: 33128

American (AMR) AF: 0.179 AC: 7774 AN: 43372

Ashkenazi Jewish (ASJ) AF: 0.00582 AC: 151 AN: 25930

East Asian (EAS) AF: 0.222 AC: 8705 AN: 39268

South Asian (SAS) AF: 0.0410 AC: 3487 AN: 85104

European-Finnish (FIN) AF: 0.00242 AC: 128 AN: 52808

Middle Eastern (MID) AF: 0.00305 AC: 13 AN: 4256

European-Non Finnish (NFE) AF: 0.000769 AC: 850 AN: 1104980

Other (OTH) AF: 0.0231 AC: 1381 AN: 59796

GnomAD4 genome AF: 0.0287 AC: 4364 AN: 152318 Hom.: 276 Cov.: 33 AF XY: 0.0306 AC XY: 2276 AN XY: 74480

African (AFR) AF: 0.0299 AC: 1241 AN: 41574

American (AMR) AF: 0.0988 AC: 1512 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.236 AC: 1215 AN: 5154

South Asian (SAS) AF: 0.0452 AC: 218 AN: 4826

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68038

Other (OTH) AF: 0.0250 AC: 53 AN: 2116

Alfa AF: 0.0111 Hom.: 16

Bravo AF: 0.0396

Asia WGS AF: 0.130 AC: 452 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.46
PhyloP100		-1.2
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: rs11101192; hg19: chr10-50854767; COSMIC: COSV60335717;