10-49625629-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_020549.5(CHAT):​c.909C>T​(p.His303His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000541 in 1,581,602 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (1 hom.)
• Consequence: CHAT NM_020549.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 10-49625629-C-T is Benign according to our data. Variant chr10-49625629-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 497741.
• BP7: Synonymous conserved (PhyloP=-0.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00127 (194/152334) while in subpopulation AMR AF = 0.00274 (42/15306). AF 95% confidence interval is 0.00224. There are 0 homozygotes in GnomAd4. There are 102 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	NM_020549.5	MANE Select	c.909C>T	p.His303His	synonymous	Exon 6 of 15	NP_065574.4
	CHAT	NM_001142933.2		c.663C>T	p.His221His	synonymous	Exon 7 of 16	NP_001136405.2
	CHAT	NM_001142929.2		c.555C>T	p.His185His	synonymous	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>T	p.His303His	synonymous	Exon 6 of 15	ENSP00000337103.2
	CHAT	ENST00000395562.2	TSL:1	c.663C>T	p.His221His	synonymous	Exon 7 of 16	ENSP00000378929.2
	CHAT	ENST00000339797.5	TSL:1	c.555C>T	p.His185His	synonymous	Exon 6 of 15	ENSP00000343486.1

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000730 AC: 143 AN: 195844 AF XY: 0.000747

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00442

Gnomad EAS exome AF: 0.0000682

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000252

Gnomad OTH exome AF: 0.00136

GnomAD4 exome AF: 0.000463 AC: 662 AN: 1429268 Hom.: 1 Cov.: 32 AF XY: 0.000465 AC XY: 329 AN XY: 707788

African (AFR) AF: 0.00286 AC: 94 AN: 32822

American (AMR) AF: 0.00196 AC: 78 AN: 39696

Ashkenazi Jewish (ASJ) AF: 0.00392 AC: 100 AN: 25492

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38240

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51168

Middle Eastern (MID) AF: 0.00227 AC: 13 AN: 5736

European-Non Finnish (NFE) AF: 0.000289 AC: 316 AN: 1094810

Other (OTH) AF: 0.000997 AC: 59 AN: 59204

GnomAD4 genome AF: 0.00127 AC: 194 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.00137 AC XY: 102 AN XY: 74496

African (AFR) AF: 0.00265 AC: 110 AN: 41582

American (AMR) AF: 0.00274 AC: 42 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.000950 Hom.: 1

Bravo AF: 0.00174

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.3
DANN	Benign	0.56
PhyloP100		-0.030
Mutation Taster		=96/4	polymorphism

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;