10-49620580-G-C

Variant names:

• chr10-49620580-G-C
• rs8178989
• NM_020549.5:c.665G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_020549.5(CHAT):​c.665G>C​(p.Arg222Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,613,606 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R222Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: CHAT NM_020549.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 0.151
• Publications: 4 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02284494).
• BP6: Variant 10-49620580-G-C is Benign according to our data. Variant chr10-49620580-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 421843.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00133 (203/152230) while in subpopulation AMR AF = 0.00536 (82/15302). AF 95% confidence interval is 0.00442. There are 0 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.665G>C	p.Arg222Pro	missense	Exon 4 of 15	NP_065574.4	P28329-1
	CHAT	NM_001142933.2		c.419G>C	p.Arg140Pro	missense	Exon 5 of 16	NP_001136405.2	P28329-2
	CHAT	NM_001142929.2		c.311G>C	p.Arg104Pro	missense	Exon 4 of 15	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.665G>C	p.Arg222Pro	missense	Exon 4 of 15	ENSP00000337103.2	P28329-1
	CHAT	ENST00000395562.2	TSL:1	c.419G>C	p.Arg140Pro	missense	Exon 5 of 16	ENSP00000378929.2	P28329-2
	CHAT	ENST00000339797.5	TSL:1	c.311G>C	p.Arg104Pro	missense	Exon 4 of 15	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000811 AC: 204 AN: 251436 AF XY: 0.000817

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.00123 AC: 1798 AN: 1461376 Hom.: 1 Cov.: 31 AF XY: 0.00124 AC XY: 900 AN XY: 726998

African (AFR) AF: 0.000329 AC: 11 AN: 33476

American (AMR) AF: 0.00134 AC: 60 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86232

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53374

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00145 AC: 1611 AN: 1111682

Other (OTH) AF: 0.00114 AC: 69 AN: 60360

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.00159 AC XY: 118 AN XY: 74442

African (AFR) AF: 0.000265 AC: 11 AN: 41526

American (AMR) AF: 0.00536 AC: 82 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00156 AC: 106 AN: 67996

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.00147

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000717 AC: 87

EpiCase AF: 0.00158

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Familial infantile myasthenia (3)
-	3	-	not provided (3)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.023	T
MetaSVM	Uncertain	-0.024	T
MutationAssessor	Benign	0.98	L
PhyloP100		0.15
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.69
Sift	Benign	0.17	T
Sift4G	Benign	0.094	T
Polyphen		0.98	D
Vest4		0.20
MVP		0.87
MPC		0.42
ClinPred		0.020	T
GERP RS		1.6
Varity_R		0.45
gMVP		0.71
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs8178989; hg19: chr10-50828626;