rs116071049

chr10-49646641-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_020549.5(CHAT):c.1248C>T(p.Asn416=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,614,068 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (11 hom.)
• Consequence: CHAT NM_020549.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -1.82

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 10-49646641-C-T is Benign according to our data. Variant chr10-49646641-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198893.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-1.82 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00182 (277/152346) while in subpopulation NFE AF= 0.00247 (168/68034). AF 95% confidence interval is 0.00216. There are 0 homozygotes in gnomad4. There are 126 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHAT	NM_020549.5	c.1248C>T	p.Asn416=	synonymous_variant	8/15	ENST00000337653.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHAT	ENST00000337653.7	c.1248C>T	p.Asn416=	synonymous_variant	8/15	1	NM_020549.5	P2

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 277 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00247

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00150 AC: 377 AN: 251180 Hom.: 0 AF XY: 0.00147 AC XY: 199 AN XY: 135826

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00239

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00223

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00277 AC: 4054 AN: 1461722 Hom.: 11 Cov.: 32 AF XY: 0.00265 AC XY: 1925 AN XY: 727160

Gnomad4 AFR exome AF: 0.00263

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00113

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00326

Gnomad4 OTH exome AF: 0.00399

GnomAD4 genome AF: 0.00182 AC: 277 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.00169 AC XY: 126 AN XY: 74496

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00247

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00173 Hom.: 0

Bravo AF: 0.00235

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 08, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 08, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	CHAT: BP4, BP7 -

Familial infantile myasthenia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	0.49
Dann	Benign	0.93

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: rs116071049; hg19: chr10-50854687;