chr10-49622109-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020549.5(CHAT):c.711C>G(p.Ser237Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00465 in 1,262,450 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 5 hom., cov: 16)

Exomes 𝑓: 0.0045 ( 16 hom. )

Consequence

CHAT
NM_020549.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.808

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008769691).

BP6

Variant 10-49622109-C-G is Benign according to our data. Variant chr10-49622109-C-G is described in ClinVar as [Benign]. Clinvar id is 128725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00813 (496/61012) while in subpopulation EAS AF= 0.0223 (45/2016). AF 95% confidence interval is 0.0171. There are 5 homozygotes in gnomad4. There are 274 alleles in male gnomad4 subpopulation. Median coverage is 16. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5 link	c.711C>G	p.Ser237Arg	missense_variant	Exon 5 of 15	ENST00000337653.7	NP_065574.4	P28329-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7 link	c.711C>G	p.Ser237Arg	missense_variant	Exon 5 of 15	1	NM_020549.5	ENSP00000337103.2		P28329-1

Frequencies

GnomAD3 genomes

AF:

0.00814

AC:

496

AN:

60938

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00237

Gnomad ASJ

AF:

0.00581

Gnomad EAS

AF:

0.0223

Gnomad SAS

AF:

0.00314

Gnomad FIN

AF:

0.0438

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00792

Gnomad OTH

AF:

0.0123

GnomAD3 exomes

AF:

0.00381

AC:

957

AN:

251334

Hom.:

AF XY:

0.00388

AC XY:

527

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.000867

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00886

Gnomad SAS exome

AF:

0.00186

Gnomad FIN exome

AF:

0.0122

Gnomad NFE exome

AF:

0.00355

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00447

AC:

5373

AN:

1201438

Hom.:

Cov.:

AF XY:

0.00451

AC XY:

2672

AN XY:

592458

show subpopulations

Gnomad4 AFR exome

AF:

0.000676

Gnomad4 AMR exome

AF:

0.000857

Gnomad4 ASJ exome

AF:

0.00301

Gnomad4 EAS exome

AF:

0.0144

Gnomad4 SAS exome

AF:

0.00230

Gnomad4 FIN exome

AF:

0.0173

Gnomad4 NFE exome

AF:

0.00417

Gnomad4 OTH exome

AF:

0.00544

GnomAD4 genome

AF:

0.00813

AC:

496

AN:

61012

Hom.:

Cov.:

AF XY:

0.00934

AC XY:

274

AN XY:

29336

show subpopulations

Gnomad4 AFR

AF:

0.00199

Gnomad4 AMR

AF:

0.00236

Gnomad4 ASJ

AF:

0.00581

Gnomad4 EAS

AF:

0.0223

Gnomad4 SAS

AF:

0.00315

Gnomad4 FIN

AF:

0.0438

Gnomad4 NFE

AF:

0.00792

Gnomad4 OTH

AF:

0.0121

Alfa

AF:

0.00338

Hom.:

Bravo

AF:

0.00238

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00369

AC:

448

Asia WGS

AF:

0.00549

AC:

AN:

3472

EpiCase

AF:

0.00371

EpiControl

AF:

0.00338

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CHAT: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:2

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial infantile myasthenia

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.22

.;.;.;T;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.88

.;.;D;D;D

MetaRNN

Benign

0.0088

T;T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.050

.;.;.;N;.

PrimateAI

Benign

0.29

PROVEAN

Benign

1.5

N;N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.40

T;T;T;T;T

Sift4G

Benign

0.43

T;T;T;T;T

Polyphen

0.021

.;.;.;B;.

Vest4

0.33

MutPred

0.62

.;.;.;Gain of methylation at S237 (P = 0.0238);.;

MVP

0.88

MPC

0.29

ClinPred

0.010

GERP RS

3.8

Varity_R

0.20

gMVP

0.45

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over