rs1554809701

Variant names:

• chr10-49664979-C-A
• rs1554809701
• NM_020549.5:c.2180C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020549.5(CHAT):​c.2180C>A​(p.Pro727His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHAT NM_020549.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.812
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12905511).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5	c.2180C>A	p.Pro727His	missense_variant	Exon 15 of 15	ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7	c.2180C>A	p.Pro727His	missense_variant	Exon 15 of 15	1	NM_020549.5	ENSP00000337103.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial infantile myasthenia Uncertain:1

Feb 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 727 of the CHAT protein (p.Pro727His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHAT-related conditions. ClinVar contains an entry for this variant (Variation ID: 461455). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CHAT protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.098	.;.;.;T;.;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.41	.;.;T;T;T;T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.7	.;.;.;L;.;.
PhyloP100		0.81
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.070	N;N;N;N;N;.
REVEL	Benign	0.21
Sift	Uncertain	0.016	D;D;D;D;D;.
Sift4G	Benign	0.085	T;T;T;D;T;.
Polyphen		0.87	.;.;.;P;.;.
Vest4		0.12
MutPred		0.20		.;.;.;Loss of catalytic residue at P726 (P = 0.0107);.;.;
MVP		0.85
MPC		0.35
ClinPred		0.35	T
GERP RS		2.8
Varity_R		0.17
gMVP		0.20
Mutation Taster		=85/15	polymorphism

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: rs1554809701; hg19: chr10-50873025;