chr10-49620460-G-A

Variant names:

• chr10-49620460-G-A
• rs1880677
• NM_020549.5:c.580-35G>A

Variant summary

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

The NM_020549.5(CHAT):​c.580-35G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,402,166 control chromosomes in the GnomAD database, including 687,724 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (72504 hom., cov: 32)
  • Exomes 𝑓: 0.99 (615220 hom.)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0190
• Publications: 6 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=-0.89).
• BP6: Variant 10-49620460-G-A is Benign according to our data. Variant chr10-49620460-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.989 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	NM_020549.5	MANE Select	c.580-35G>A		intron	N/A	NP_065574.4
	CHAT	NM_001142933.2		c.334-35G>A		intron	N/A	NP_001136405.2
	CHAT	NM_001142929.2		c.226-35G>A		intron	N/A	NP_001136401.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	ENST00000337653.7	TSL:1 MANE Select	c.580-35G>A		intron	N/A	ENSP00000337103.2
	CHAT	ENST00000395562.2	TSL:1	c.334-35G>A		intron	N/A	ENSP00000378929.2
	CHAT	ENST00000339797.5	TSL:1	c.226-35G>A		intron	N/A	ENSP00000343486.1

Frequencies

GnomAD3 genomes AF: 0.976 AC: 148381 AN: 152096 Hom.: 72445 Cov.: 32

Gnomad AFR AF: 0.928

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.986

Gnomad ASJ AF: 0.992

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.969

Gnomad FIN AF: 0.999

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.996

Gnomad OTH AF: 0.976

GnomAD2 exomes AF: 0.987 AC: 246908 AN: 250088 AF XY: 0.987

Gnomad AFR exome AF: 0.927

Gnomad AMR exome AF: 0.992

Gnomad ASJ exome AF: 0.993

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.999

Gnomad NFE exome AF: 0.995

Gnomad OTH exome AF: 0.986

GnomAD4 exome AF: 0.992 AC: 1240024 AN: 1249952 Hom.: 615220 Cov.: 17 AF XY: 0.991 AC XY: 627515 AN XY: 632972

African (AFR) AF: 0.926 AC: 27024 AN: 29190

American (AMR) AF: 0.991 AC: 44045 AN: 44432

Ashkenazi Jewish (ASJ) AF: 0.994 AC: 24534 AN: 24694

East Asian (EAS) AF: 1.00 AC: 38412 AN: 38416

South Asian (SAS) AF: 0.968 AC: 79381 AN: 81966

European-Finnish (FIN) AF: 0.999 AC: 50973 AN: 51000

Middle Eastern (MID) AF: 0.972 AC: 5209 AN: 5358

European-Non Finnish (NFE) AF: 0.996 AC: 917573 AN: 921444

Other (OTH) AF: 0.989 AC: 52873 AN: 53452

GnomAD4 genome AF: 0.976 AC: 148499 AN: 152214 Hom.: 72504 Cov.: 32 AF XY: 0.976 AC XY: 72605 AN XY: 74428

African (AFR) AF: 0.929 AC: 38552 AN: 41518

American (AMR) AF: 0.986 AC: 15093 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.992 AC: 3443 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5148 AN: 5148

South Asian (SAS) AF: 0.968 AC: 4670 AN: 4822

European-Finnish (FIN) AF: 0.999 AC: 10618 AN: 10624

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.996 AC: 67715 AN: 68010

Other (OTH) AF: 0.976 AC: 2060 AN: 2110

Alfa AF: 0.987 Hom.: 19522

Bravo AF: 0.973

Asia WGS AF: 0.983 AC: 3420 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.2
DANN	Benign	0.83
PhyloP100		0.019
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1880677; hg19: chr10-50828506;