10-49620580-G-C

Position:

• chr10-49620580-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_020549.5(CHAT):​c.665G>C​(p.Arg222Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,613,606 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: CHAT NM_020549.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 0.151

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02284494).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00133 (203/152230) while in subpopulation AMR AF= 0.00536 (82/15302). AF 95% confidence interval is 0.00442. There are 0 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHAT	NM_020549.5	c.665G>C	p.Arg222Pro	missense_variant	4/15	ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7	c.665G>C	p.Arg222Pro	missense_variant	4/15	1	NM_020549.5	ENSP00000337103	P2

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000811 AC: 204 AN: 251436 Hom.: 0 AF XY: 0.000817 AC XY: 111 AN XY: 135892

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.00123 AC: 1798 AN: 1461376 Hom.: 1 Cov.: 31 AF XY: 0.00124 AC XY: 900 AN XY: 726998

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00145

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.00159 AC XY: 118 AN XY: 74442

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.00147

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000717 AC: 87

EpiCase AF: 0.00158

EpiControl AF: 0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial infantile myasthenia Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 20, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 12, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2017	The R222P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, nor was it observed with any significant frequency in the 1000 Genomes Project. The R222P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with CHAT-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 16, 2018	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 10, 2016

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.665G>C (p.R222P) alteration is located in exon 4 (coding exon 4) of the CHAT gene. This alteration results from a G to C substitution at nucleotide position 665, causing the arginine (R) at amino acid position 222 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	.;.;.;T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.70	.;.;T;T;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.023	T;T;T;T;T
MetaSVM	Uncertain	-0.024	T
MutationAssessor	Benign	0.98	.;.;.;L;.
MutationTaster	Benign	0.93	D;D;D;D;D;D
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.9	N;N;N;N;N
REVEL	Pathogenic	0.69
Sift	Benign	0.17	T;T;T;T;T
Sift4G	Benign	0.094	T;T;T;T;T
Polyphen		0.98	.;.;.;D;.
Vest4		0.20
MVP		0.87
MPC		0.42
ClinPred		0.020	T
GERP RS		1.6
Varity_R		0.45
gMVP		0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs8178989; hg19: chr10-50828626;