rs114719193

Positions:

• chr10-49665021-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_020549.5(CHAT):​c.2222G>A​(p.Arg741Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 1,614,072 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.00035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: CHAT NM_020549.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 0.647

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021799117).
• BP6: Variant 10-49665021-G-A is Benign according to our data. Variant chr10-49665021-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287910.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000262 (383/1461794) while in subpopulation MID AF= 0.00368 (21/5708). AF 95% confidence interval is 0.00247. There are 1 homozygotes in gnomad4_exome. There are 214 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHAT	NM_020549.5	c.2222G>A	p.Arg741Lys	missense_variant	15/15	ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7	c.2222G>A	p.Arg741Lys	missense_variant	15/15	1	NM_020549.5	ENSP00000337103.2

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152160 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000338 AC: 85 AN: 251242 Hom.: 0 AF XY: 0.000442 AC XY: 60 AN XY: 135854

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000262 AC: 383 AN: 1461794 Hom.: 1 Cov.: 32 AF XY: 0.000294 AC XY: 214 AN XY: 727192

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000870

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000195

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152278 Hom.: 1 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74440

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00799 Hom.: 823

Bravo AF: 0.000366

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000354 AC: 43

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 21, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2020	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 04, 2018	- -

Familial infantile myasthenia Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 10, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	9.7
DANN	Benign	0.88
DEOGEN2	Benign	0.076	.;.;.;T;.;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.49	.;.;T;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.022	T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.3	.;.;.;L;.;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.0	N;N;N;N;N;.
REVEL	Benign	0.098
Sift	Benign	0.55	T;T;T;T;T;.
Sift4G	Benign	0.67	T;T;T;T;T;.
Polyphen		0.0050	.;.;.;B;.;.
Vest4		0.10
MVP		0.79
MPC		0.25
ClinPred		0.0061	T
GERP RS		1.2
Varity_R		0.047
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs114719193; hg19: chr10-50873067;