rs78925077

Variant names:

• chr10-49622109-C-G
• rs78925077
• NM_020549.5:c.711C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000337653.7(CHAT):​c.711C>G​(p.Ser237Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00465 in 1,262,450 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (5 hom., cov: 16)
  • Exomes 𝑓: 0.0045 (16 hom.)
• Consequence: CHAT ENST00000337653.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.808
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008769691).
• BP6: Variant 10-49622109-C-G is Benign according to our data. Variant chr10-49622109-C-G is described in ClinVar as Benign. ClinVar VariationId is 128725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00813 (496/61012) while in subpopulation EAS AF = 0.0223 (45/2016). AF 95% confidence interval is 0.0171. There are 5 homozygotes in GnomAd4. There are 274 alleles in the male GnomAd4 subpopulation. Median coverage is 16. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000337653.7. 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.711C>G	p.Ser237Arg	missense	Exon 5 of 15	NP_065574.4
	CHAT	NM_001142933.2		c.465C>G	p.Ser155Arg	missense	Exon 6 of 16	NP_001136405.2
	CHAT	NM_001142929.2		c.357C>G	p.Ser119Arg	missense	Exon 5 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.711C>G	p.Ser237Arg	missense	Exon 5 of 15	ENSP00000337103.2
	CHAT	ENST00000395562.2	TSL:1	c.465C>G	p.Ser155Arg	missense	Exon 6 of 16	ENSP00000378929.2
	CHAT	ENST00000339797.5	TSL:1	c.357C>G	p.Ser119Arg	missense	Exon 5 of 15	ENSP00000343486.1

Frequencies

GnomAD3 genomes AF: 0.00814 AC: 496 AN: 60938 Hom.: 5 Cov.: 16

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00237

Gnomad ASJ AF: 0.00581

Gnomad EAS AF: 0.0223

Gnomad SAS AF: 0.00314

Gnomad FIN AF: 0.0438

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00792

Gnomad OTH AF: 0.0123

GnomAD2 exomes AF: 0.00381 AC: 957 AN: 251334 AF XY: 0.00388

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00886

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.00355

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00447 AC: 5373 AN: 1201438 Hom.: 16 Cov.: 37 AF XY: 0.00451 AC XY: 2672 AN XY: 592458

African (AFR) AF: 0.000676 AC: 17 AN: 25150

American (AMR) AF: 0.000857 AC: 30 AN: 35026

Ashkenazi Jewish (ASJ) AF: 0.00301 AC: 52 AN: 17276

East Asian (EAS) AF: 0.0144 AC: 270 AN: 18712

South Asian (SAS) AF: 0.00230 AC: 156 AN: 67900

European-Finnish (FIN) AF: 0.0173 AC: 612 AN: 35402

Middle Eastern (MID) AF: 0.00385 AC: 17 AN: 4418

European-Non Finnish (NFE) AF: 0.00417 AC: 3979 AN: 953432

Other (OTH) AF: 0.00544 AC: 240 AN: 44122

GnomAD4 genome AF: 0.00813 AC: 496 AN: 61012 Hom.: 5 Cov.: 16 AF XY: 0.00934 AC XY: 274 AN XY: 29336

African (AFR) AF: 0.00199 AC: 31 AN: 15584

American (AMR) AF: 0.00236 AC: 12 AN: 5076

Ashkenazi Jewish (ASJ) AF: 0.00581 AC: 9 AN: 1548

East Asian (EAS) AF: 0.0223 AC: 45 AN: 2016

South Asian (SAS) AF: 0.00315 AC: 6 AN: 1906

European-Finnish (FIN) AF: 0.0438 AC: 143 AN: 3264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 80

European-Non Finnish (NFE) AF: 0.00792 AC: 241 AN: 30436

Other (OTH) AF: 0.0121 AC: 9 AN: 744

Alfa AF: 0.00338 Hom.: 0

Bravo AF: 0.00238

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00369 AC: 448

Asia WGS AF: 0.00549 AC: 19 AN: 3472

EpiCase AF: 0.00371

EpiControl AF: 0.00338

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	14
DANN	Benign	0.74
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.050	N
PhyloP100		0.81
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.19
Sift	Benign	0.40	T
Sift4G	Benign	0.43	T
Polyphen		0.021	B
Vest4		0.33
MutPred		0.62		Gain of methylation at S237 (P = 0.0238)
MVP		0.88
MPC		0.29
ClinPred		0.010	T
GERP RS		3.8
Varity_R		0.20
gMVP		0.45
Mutation Taster		=67/33	polymorphism

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: rs78925077; hg19: chr10-50830155; COSMIC: COSV107410892; COSMIC: COSV107410892;