rs12257601

Variant names:

• chr10-49625447-C-T
• rs12257601
• NM_020549.5:c.753-26C>T

Variant summary

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

The NM_020549.5(CHAT):​c.753-26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,610,322 control chromosomes in the GnomAD database, including 3,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.086 (1883 hom., cov: 33)
  • Exomes 𝑓: 0.0094 (1681 hom.)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.37

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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 10-49625447-C-T is Benign according to our data. Variant chr10-49625447-C-T is described in ClinVar as [Benign]. Clinvar id is 261338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49625447-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5	c.753-26C>T		intron_variant	Intron 5 of 14	ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7	c.753-26C>T		intron_variant	Intron 5 of 14	1	NM_020549.5	ENSP00000337103.2

Frequencies

GnomAD3 genomes AF: 0.0860 AC: 13086 AN: 152126 Hom.: 1861 Cov.: 33

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0363

Gnomad ASJ AF: 0.0204

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.0616

GnomAD3 exomes AF: 0.0231 AC: 5753 AN: 248606 Hom.: 714 AF XY: 0.0173 AC XY: 2324 AN XY: 134462

Gnomad AFR exome AF: 0.303

Gnomad AMR exome AF: 0.0150

Gnomad ASJ exome AF: 0.0195

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000725

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000962

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.00937 AC: 13662 AN: 1458078 Hom.: 1681 Cov.: 32 AF XY: 0.00809 AC XY: 5866 AN XY: 725312

Gnomad4 AFR exome AF: 0.310

Gnomad4 AMR exome AF: 0.0169

Gnomad4 ASJ exome AF: 0.0182

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000733

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000624

Gnomad4 OTH exome AF: 0.0214

GnomAD4 genome AF: 0.0864 AC: 13153 AN: 152244 Hom.: 1883 Cov.: 33 AF XY: 0.0838 AC XY: 6239 AN XY: 74446

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.0363

Gnomad4 ASJ AF: 0.0204

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.0610

Alfa AF: 0.0390 Hom.: 133

Bravo AF: 0.0993

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.0
DANN	Benign	0.83
La Branchor		0.74
BranchPoint Hunter		3.0

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: rs12257601; hg19: chr10-50833493;