rs2269338

Variant names:

• chr10-49612378-G-T
• rs2269338
• NM_003055.3:c.*39G>T

Your query was ambiguous. Multiple possible variants found:

• chr10-49612378-G-T
• chr10-49612378-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003055.3(SLC18A3):​c.*39G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,544,970 control chromosomes in the GnomAD database, including 13,709 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1667 hom., cov: 33)
  • Exomes 𝑓: 0.12 (12042 hom.)
• Consequence: SLC18A3 NM_003055.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.84
• Publications: 11 publications found

Genes affected

SLC18A3 (HGNC:10936): (solute carrier family 18 member A3) This gene is a member of the vesicular amine transporter family. The encoded transmembrane protein transports acetylcholine into secretory vesicles for release into the extracellular space. Acetylcholine transport utilizes a proton gradient established by a vacuolar ATPase. This gene is located within the first intron of the choline acetyltransferase gene. [provided by RefSeq, Jul 2008]

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 10-49612378-G-T is Benign according to our data. Variant chr10-49612378-G-T is described in ClinVar as Benign. ClinVar VariationId is 1175691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003055.3. 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
	SLC18A3	NM_003055.3	MANE Select	c.*39G>T		3_prime_UTR	Exon 1 of 1	NP_003046.2	Q16572
	CHAT	NM_020984.4		c.-69+3179G>T		intron	N/A	NP_066264.4	P28329-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC18A3	ENST00000374115.5	TSL:6 MANE Select	c.*39G>T		3_prime_UTR	Exon 1 of 1	ENSP00000363229.3	Q16572
	CHAT	ENST00000339797.5	TSL:1	c.-69+3179G>T		intron	N/A	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19787 AN: 151986 Hom.: 1666 Cov.: 33

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.0913

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.132

GnomAD2 exomes AF: 0.163 AC: 32571 AN: 199974 AF XY: 0.157

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.474

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.119 AC: 165873 AN: 1392866 Hom.: 12042 Cov.: 32 AF XY: 0.117 AC XY: 80303 AN XY: 684014

African (AFR) AF: 0.101 AC: 3219 AN: 31750

American (AMR) AF: 0.191 AC: 7262 AN: 37950

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 2900 AN: 21860

East Asian (EAS) AF: 0.397 AC: 15468 AN: 38990

South Asian (SAS) AF: 0.0888 AC: 6627 AN: 74614

European-Finnish (FIN) AF: 0.197 AC: 9864 AN: 50100

Middle Eastern (MID) AF: 0.116 AC: 630 AN: 5452

European-Non Finnish (NFE) AF: 0.105 AC: 112581 AN: 1074766

Other (OTH) AF: 0.128 AC: 7322 AN: 57384

GnomAD4 genome AF: 0.130 AC: 19796 AN: 152104 Hom.: 1667 Cov.: 33 AF XY: 0.135 AC XY: 10028 AN XY: 74376

African (AFR) AF: 0.106 AC: 4402 AN: 41496

American (AMR) AF: 0.139 AC: 2130 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 450 AN: 3468

East Asian (EAS) AF: 0.451 AC: 2324 AN: 5152

South Asian (SAS) AF: 0.0911 AC: 440 AN: 4828

European-Finnish (FIN) AF: 0.206 AC: 2177 AN: 10566

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7471 AN: 67996

Other (OTH) AF: 0.132 AC: 279 AN: 2114

Alfa AF: 0.115 Hom.: 625

Bravo AF: 0.130

Asia WGS AF: 0.247 AC: 858 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		1.8
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: rs2269338; hg19: chr10-50820424; COSMIC: COSV60320383; COSMIC: COSV60320383;