NM_020549.5:c.909C>G

Variant names:

• chr10-49625629-C-G
• rs76570508
• NM_020549.5:c.909C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_020549.5(CHAT):​c.909C>G​(p.His303Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H303H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHAT NM_020549.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0300
• Publications: 0 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: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in NM_020549.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	NM_020549.5	MANE Select	c.909C>G	p.His303Gln	missense	Exon 6 of 15	NP_065574.4
	CHAT	NM_001142933.2		c.663C>G	p.His221Gln	missense	Exon 7 of 16	NP_001136405.2
	CHAT	NM_001142929.2		c.555C>G	p.His185Gln	missense	Exon 6 of 15	NP_001136401.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	ENST00000337653.7	TSL:1 MANE Select	c.909C>G	p.His303Gln	missense	Exon 6 of 15	ENSP00000337103.2
	CHAT	ENST00000395562.2	TSL:1	c.663C>G	p.His221Gln	missense	Exon 7 of 16	ENSP00000378929.2
	CHAT	ENST00000339797.5	TSL:1	c.555C>G	p.His185Gln	missense	Exon 6 of 15	ENSP00000343486.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000511 AC: 1 AN: 195844 AF XY: 0.00

Gnomad AFR exome AF: 0.0000844

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000831 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.87	D
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		-0.030
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.80		Gain of catalytic residue at H303 (P = 0.0173)
MVP		0.93
MPC		0.89
ClinPred		0.98	D
GERP RS		-5.5
Varity_R		0.88
gMVP		0.89
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76570508; hg19: chr10-50833675;