chr10-49614173-G-A

Variant names:

• chr10-49614173-G-A
• rs77152496
• ENST00000466590.6:n.-17G>A

Variant summary

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

The ENST00000466590.6(CHAT):​n.-17G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,544,524 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (86 hom., cov: 28)
  • Exomes 𝑓: 0.0017 (59 hom.)
• Consequence: CHAT ENST00000466590.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0340
• Publications: 1 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 (BayesDel_noAF=-0.84).
• BP6: Variant 10-49614173-G-A is Benign according to our data. Variant chr10-49614173-G-A is described in ClinVar as Benign. ClinVar VariationId is 193434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0547 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000466590.6. 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.-17G>A		5_prime_UTR	Exon 1 of 15	NP_065574.4
	CHAT	NM_001142933.2		c.-333G>A		5_prime_UTR	Exon 1 of 16	NP_001136405.2
	CHAT	NM_001142929.2		c.-371G>A		5_prime_UTR	Exon 1 of 15	NP_001136401.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	ENST00000466590.6	TSL:1	n.-17G>A		non_coding_transcript_exon	Exon 1 of 16	ENSP00000473443.1
	CHAT	ENST00000337653.7	TSL:1 MANE Select	c.-17G>A		5_prime_UTR	Exon 1 of 15	ENSP00000337103.2
	CHAT	ENST00000395562.2	TSL:1	c.-333G>A		5_prime_UTR	Exon 1 of 16	ENSP00000378929.2

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2457 AN: 151526 Hom.: 84 Cov.: 28

Gnomad AFR AF: 0.0565

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00650

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0111

GnomAD2 exomes AF: 0.00337 AC: 480 AN: 142228 AF XY: 0.00287

Gnomad AFR exome AF: 0.0608

Gnomad AMR exome AF: 0.00308

Gnomad ASJ exome AF: 0.000122

Gnomad EAS exome AF: 0.000189

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000214

Gnomad OTH exome AF: 0.00145

GnomAD4 exome AF: 0.00172 AC: 2390 AN: 1392882 Hom.: 59 Cov.: 37 AF XY: 0.00148 AC XY: 1018 AN XY: 687072

African (AFR) AF: 0.0588 AC: 1852 AN: 31508

American (AMR) AF: 0.00361 AC: 127 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.0000398 AC: 1 AN: 25124

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35718

South Asian (SAS) AF: 0.000316 AC: 25 AN: 79108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47292

Middle Eastern (MID) AF: 0.00267 AC: 11 AN: 4118

European-Non Finnish (NFE) AF: 0.000129 AC: 139 AN: 1077094

Other (OTH) AF: 0.00405 AC: 234 AN: 57720

GnomAD4 genome AF: 0.0163 AC: 2467 AN: 151642 Hom.: 86 Cov.: 28 AF XY: 0.0154 AC XY: 1141 AN XY: 74118

African (AFR) AF: 0.0566 AC: 2332 AN: 41204

American (AMR) AF: 0.00649 AC: 99 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5144

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67926

Other (OTH) AF: 0.0110 AC: 23 AN: 2094

Alfa AF: 0.00830 Hom.: 5

Bravo AF: 0.0189

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.5
DANN	Benign	0.82
PhyloP100		0.034
PromoterAI		-0.0088	Neutral
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: rs77152496; hg19: chr10-50822219;