chr10-49644481-G-C

Variant names:

• chr10-49644481-G-C
• rs7903612
• NM_020549.5:c.1112-2024G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020549.5(CHAT):​c.1112-2024G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 152,126 control chromosomes in the GnomAD database, including 6,491 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (6491 hom., cov: 33)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.249
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020549.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	NM_020549.5	MANE Select	c.1112-2024G>C		intron	N/A	NP_065574.4	P28329-1
	CHAT	NM_001142933.2		c.866-2024G>C		intron	N/A	NP_001136405.2	P28329-2
	CHAT	NM_001142929.2		c.758-2024G>C		intron	N/A	NP_001136401.2	P28329-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	ENST00000337653.7	TSL:1 MANE Select	c.1112-2024G>C		intron	N/A	ENSP00000337103.2	P28329-1
	CHAT	ENST00000395562.2	TSL:1	c.866-2024G>C		intron	N/A	ENSP00000378929.2	P28329-2
	CHAT	ENST00000339797.5	TSL:1	c.758-2024G>C		intron	N/A	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39464 AN: 152008 Hom.: 6498 Cov.: 33

Gnomad AFR AF: 0.0789

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.0648

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.285

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.259 AC: 39468 AN: 152126 Hom.: 6491 Cov.: 33 AF XY: 0.263 AC XY: 19534 AN XY: 74348

African (AFR) AF: 0.0791 AC: 3285 AN: 41526

American (AMR) AF: 0.236 AC: 3610 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1182 AN: 3472

East Asian (EAS) AF: 0.0643 AC: 333 AN: 5176

South Asian (SAS) AF: 0.215 AC: 1035 AN: 4818

European-Finnish (FIN) AF: 0.442 AC: 4675 AN: 10580

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.358 AC: 24329 AN: 67948

Other (OTH) AF: 0.282 AC: 597 AN: 2116

Alfa AF: 0.220 Hom.: 605

Bravo AF: 0.234

Asia WGS AF: 0.128 AC: 448 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.72
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7903612; hg19: chr10-50852527;