rs115126024

Variant names:

• chr10-49646524-G-A
• rs115126024
• NM_020549.5:c.1131G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-49646524-G-A
• chr10-49646524-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020549.5(CHAT):​c.1131G>A​(p.Ser377Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,614,172 control chromosomes in the GnomAD database, including 184 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (94 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (90 hom.)
• Consequence: CHAT NM_020549.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.55
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 10-49646524-G-A is Benign according to our data. Variant chr10-49646524-G-A is described in ClinVar as Benign. ClinVar VariationId is 128716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0623 is higher than 0.05.

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.1131G>A	p.Ser377Ser	synonymous	Exon 8 of 15	NP_065574.4
	CHAT	NM_001142933.2		c.885G>A	p.Ser295Ser	synonymous	Exon 9 of 16	NP_001136405.2
	CHAT	NM_001142929.2		c.777G>A	p.Ser259Ser	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.1131G>A	p.Ser377Ser	synonymous	Exon 8 of 15	ENSP00000337103.2
	CHAT	ENST00000395562.2	TSL:1	c.885G>A	p.Ser295Ser	synonymous	Exon 9 of 16	ENSP00000378929.2
	CHAT	ENST00000339797.5	TSL:1	c.777G>A	p.Ser259Ser	synonymous	Exon 8 of 15	ENSP00000343486.1

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2874 AN: 152208 Hom.: 94 Cov.: 33

Gnomad AFR AF: 0.0645

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00955

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00519 AC: 1305 AN: 251316 AF XY: 0.00380

Gnomad AFR exome AF: 0.0669

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00213 AC: 3114 AN: 1461848 Hom.: 90 Cov.: 32 AF XY: 0.00186 AC XY: 1351 AN XY: 727228

African (AFR) AF: 0.0672 AC: 2250 AN: 33472

American (AMR) AF: 0.00449 AC: 201 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000464 AC: 40 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.000278 AC: 309 AN: 1112008

Other (OTH) AF: 0.00502 AC: 303 AN: 60396

GnomAD4 genome AF: 0.0189 AC: 2878 AN: 152324 Hom.: 94 Cov.: 33 AF XY: 0.0182 AC XY: 1354 AN XY: 74490

African (AFR) AF: 0.0644 AC: 2675 AN: 41552

American (AMR) AF: 0.00954 AC: 146 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68038

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

Alfa AF: 0.0102 Hom.: 18

Bravo AF: 0.0220

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.41
DANN	Benign	0.88
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs115126024; hg19: chr10-50854570;