rs75466054

Positions:

• chr10-49625634-T-C
• chr10-49625634-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_020549.5(CHAT):​c.914T>C​(p.Ile305Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. I305I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHAT NM_020549.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 8.00

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 10-49625634-T-C is Pathogenic according to our data. Variant chr10-49625634-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 17513.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-49625634-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHAT	NM_020549.5	c.914T>C	p.Ile305Thr	missense_variant	6/15	ENST00000337653.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHAT	ENST00000337653.7	c.914T>C	p.Ile305Thr	missense_variant	6/15	1	NM_020549.5	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial infantile myasthenia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 13, 2001

- -

Congenital myasthenic syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	.;.;.;D;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;.;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	-0.017	T
MutationAssessor	Benign	1.2	.;.;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D
REVEL	Pathogenic	0.76
Sift	Benign	0.50	T;T;T;T;T
Sift4G	Benign	0.39	T;T;T;T;T
Polyphen		1.0	.;.;.;D;.
Vest4		0.89
MutPred		0.84		.;.;.;Gain of disorder (P = 0.051);.;
MVP		0.95
MPC		0.95
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.73
gMVP		0.77

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: rs75466054; hg19: chr10-50833680; COSMIC: COSV60319529; COSMIC: COSV60319529;