rs2377871

Positions:

• chr10-49646437-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000337653.7(CHAT):​c.1112-68G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0587 in 1,586,360 control chromosomes in the GnomAD database, including 4,506 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (515 hom., cov: 33)
  • Exomes 𝑓: 0.058 (3991 hom.)
• Consequence: CHAT ENST00000337653.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.394

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-49646437-G-A is Benign according to our data. Variant chr10-49646437-G-A is described in ClinVar as [Benign]. Clinvar id is 681277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHAT	NM_020549.5	c.1112-68G>A		intron_variant		ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7	c.1112-68G>A		intron_variant		1	NM_020549.5	ENSP00000337103	P2

Frequencies

GnomAD3 genomes AF: 0.0690 AC: 10501 AN: 152132 Hom.: 507 Cov.: 33

Gnomad AFR AF: 0.0709

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.0686

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.0918

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0389

Gnomad OTH AF: 0.0613

GnomAD4 exome AF: 0.0576 AC: 82591 AN: 1434110 Hom.: 3991 AF XY: 0.0593 AC XY: 42398 AN XY: 715040

Gnomad4 AFR exome AF: 0.0730

Gnomad4 AMR exome AF: 0.176

Gnomad4 ASJ exome AF: 0.0726

Gnomad4 EAS exome AF: 0.217

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.0905

Gnomad4 NFE exome AF: 0.0383

Gnomad4 OTH exome AF: 0.0660

GnomAD4 genome AF: 0.0692 AC: 10541 AN: 152250 Hom.: 515 Cov.: 33 AF XY: 0.0744 AC XY: 5538 AN XY: 74430

Gnomad4 AFR AF: 0.0711

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.0686

Gnomad4 EAS AF: 0.186

Gnomad4 SAS AF: 0.143

Gnomad4 FIN AF: 0.0918

Gnomad4 NFE AF: 0.0389

Gnomad4 OTH AF: 0.0673

Alfa AF: 0.0523 Hom.: 40

Bravo AF: 0.0728

Asia WGS AF: 0.148 AC: 512 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.4
DANN	Benign	0.50

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: rs2377871; hg19: chr10-50854483; COSMIC: COSV60324213;