rs114545628

chr10-49662688-G-Achr10-49662688-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_020549.5(CHAT):c.1883G>A(p.Arg628Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000696 in 1,614,188 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R628W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (0 hom.)
• Consequence: CHAT NM_020549.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 8.15

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 10-49662688-G-A is Benign according to our data. Variant chr10-49662688-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194422.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHAT	NM_020549.5	c.1883G>A	p.Arg628Gln	missense_variant	14/15	ENST00000337653.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHAT	ENST00000337653.7	c.1883G>A	p.Arg628Gln	missense_variant	14/15	1	NM_020549.5	P2

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000338 AC: 85 AN: 251482 Hom.: 0 AF XY: 0.000243 AC XY: 33 AN XY: 135916

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000633

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000729 AC: 1065 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.000681 AC XY: 495 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000926

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74494

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000675 Hom.: 0

Bravo AF: 0.000329

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.000545

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial infantile myasthenia Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 12, 2023	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 28, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.0016	T
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.5	N;N;N;N;N;.
REVEL	Pathogenic	0.76
Sift	Benign	0.074	T;T;T;D;D;.
Sift4G	Benign	0.093	T;T;T;T;T;.
Polyphen		1.0	.;.;.;D;.;.
Vest4		0.59
MVP		0.97
MPC		0.59
ClinPred		0.85	D
GERP RS		4.7
Varity_R		0.61
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs114545628; hg19: chr10-50870734; COSMIC: COSV60320905;