chr10-49646641-C-T

Variant names:

• chr10-49646641-C-T
• rs116071049
• NM_020549.5:c.1248C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_020549.5(CHAT):​c.1248C>T​(p.Asn416Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,614,068 control chromosomes in the GnomAD database, including 11 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 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (11 hom.)
• Consequence: CHAT NM_020549.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -1.82
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 10-49646641-C-T is Benign according to our data. Variant chr10-49646641-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198893.
• BP7: Synonymous conserved (PhyloP=-1.82 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00182 (277/152346) while in subpopulation NFE AF = 0.00247 (168/68034). AF 95% confidence interval is 0.00216. There are 0 homozygotes in GnomAd4. There are 126 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR,AD gene

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.1248C>T	p.Asn416Asn	synonymous	Exon 8 of 15	NP_065574.4
	CHAT	NM_001142933.2		c.1002C>T	p.Asn334Asn	synonymous	Exon 9 of 16	NP_001136405.2
	CHAT	NM_001142929.2		c.894C>T	p.Asn298Asn	synonymous	Exon 8 of 15	NP_001136401.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	ENST00000337653.7	TSL:1 MANE Select	c.1248C>T	p.Asn416Asn	synonymous	Exon 8 of 15	ENSP00000337103.2
	CHAT	ENST00000395562.2	TSL:1	c.1002C>T	p.Asn334Asn	synonymous	Exon 9 of 16	ENSP00000378929.2
	CHAT	ENST00000339797.5	TSL:1	c.894C>T	p.Asn298Asn	synonymous	Exon 8 of 15	ENSP00000343486.1

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 277 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00247

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00150 AC: 377 AN: 251180 AF XY: 0.00147

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00239

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00223

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00277 AC: 4054 AN: 1461722 Hom.: 11 Cov.: 32 AF XY: 0.00265 AC XY: 1925 AN XY: 727160

African (AFR) AF: 0.00263 AC: 88 AN: 33476

American (AMR) AF: 0.000961 AC: 43 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00113 AC: 45 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53412

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5642

European-Non Finnish (NFE) AF: 0.00326 AC: 3620 AN: 1112008

Other (OTH) AF: 0.00399 AC: 241 AN: 60374

GnomAD4 genome AF: 0.00182 AC: 277 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.00169 AC XY: 126 AN XY: 74496

African (AFR) AF: 0.00204 AC: 85 AN: 41582

American (AMR) AF: 0.000523 AC: 8 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00247 AC: 168 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00173 Hom.: 0

Bravo AF: 0.00235

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00196

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	Familial infantile myasthenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.49
DANN	Benign	0.93
PhyloP100		-1.8
Mutation Taster		=100/0	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: rs116071049; hg19: chr10-50854687;