rs2377871

Variant names:

• chr10-49646437-G-A
• rs2377871
• NM_020549.5:c.1112-68G>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.1112-68G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0587 in 1,586,360 control chromosomes in the GnomAD database, including 4,506 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (515 hom., cov: 33)
  • Exomes 𝑓: 0.058 (3991 hom.)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.394
• Publications: 4 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=-0.82).
• BP6: Variant 10-49646437-G-A is Benign according to our data. Variant chr10-49646437-G-A is described in ClinVar as Benign. ClinVar VariationId is 681277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5	c.1112-68G>A		intron_variant	Intron 7 of 14	ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7	c.1112-68G>A		intron_variant	Intron 7 of 14	1	NM_020549.5	ENSP00000337103.2

Frequencies

GnomAD3 genomes AF: 0.0690 AC: 10501 AN: 152132 Hom.: 507 Cov.: 33

Gnomad AFR AF: 0.0709

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.0686

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.0918

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0389

Gnomad OTH AF: 0.0613

GnomAD4 exome AF: 0.0576 AC: 82591 AN: 1434110 Hom.: 3991 AF XY: 0.0593 AC XY: 42398 AN XY: 715040

African (AFR) AF: 0.0730 AC: 2397 AN: 32828

American (AMR) AF: 0.176 AC: 7873 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0726 AC: 1886 AN: 25984

East Asian (EAS) AF: 0.217 AC: 8604 AN: 39560

South Asian (SAS) AF: 0.132 AC: 11266 AN: 85606

European-Finnish (FIN) AF: 0.0905 AC: 4537 AN: 50116

Middle Eastern (MID) AF: 0.0600 AC: 343 AN: 5720

European-Non Finnish (NFE) AF: 0.0383 AC: 41759 AN: 1090088

Other (OTH) AF: 0.0660 AC: 3926 AN: 59516

GnomAD4 genome AF: 0.0692 AC: 10541 AN: 152250 Hom.: 515 Cov.: 33 AF XY: 0.0744 AC XY: 5538 AN XY: 74430

African (AFR) AF: 0.0711 AC: 2955 AN: 41568

American (AMR) AF: 0.125 AC: 1908 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0686 AC: 238 AN: 3468

East Asian (EAS) AF: 0.186 AC: 958 AN: 5148

South Asian (SAS) AF: 0.143 AC: 689 AN: 4826

European-Finnish (FIN) AF: 0.0918 AC: 975 AN: 10616

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0389 AC: 2644 AN: 68002

Other (OTH) AF: 0.0673 AC: 142 AN: 2110

Alfa AF: 0.0530 Hom.: 41

Bravo AF: 0.0728

Asia WGS AF: 0.148 AC: 512 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.4
DANN	Benign	0.50
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2377871; hg19: chr10-50854483; COSMIC: COSV60324213;