chr10-49614180-T-G

Variant names:

• chr10-49614180-T-G
• rs7923716
• ENST00000466590.6:n.-10T>G

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.-10T>G 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 0.994 in 1,542,478 control chromosomes in the GnomAD database, including 761,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (70867 hom., cov: 20)
  • Exomes 𝑓: 1.0 (690623 hom.)
• Consequence: CHAT ENST00000466590.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.08
• Publications: 7 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=-1.0).
• BP6: Variant 10-49614180-T-G is Benign according to our data. Variant chr10-49614180-T-G is described in ClinVar as Benign. ClinVar VariationId is 193433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 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.-10T>G		5_prime_UTR	Exon 1 of 15	NP_065574.4
	CHAT	NM_001142933.2		c.-326T>G		5_prime_UTR	Exon 1 of 16	NP_001136405.2
	CHAT	NM_001142929.2		c.-364T>G		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.-10T>G		non_coding_transcript_exon	Exon 1 of 16	ENSP00000473443.1
	CHAT	ENST00000337653.7	TSL:1 MANE Select	c.-10T>G		5_prime_UTR	Exon 1 of 15	ENSP00000337103.2
	CHAT	ENST00000395562.2	TSL:1	c.-326T>G		5_prime_UTR	Exon 1 of 16	ENSP00000378929.2

Frequencies

GnomAD3 genomes AF: 0.978 AC: 144798 AN: 148030 Hom.: 70808 Cov.: 20

Gnomad AFR AF: 0.930

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.987

Gnomad ASJ AF: 0.995

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.992

Gnomad FIN AF: 0.999

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.977

GnomAD2 exomes AF: 0.993 AC: 141808 AN: 142834 AF XY: 0.993

Gnomad AFR exome AF: 0.922

Gnomad AMR exome AF: 0.994

Gnomad ASJ exome AF: 0.996

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.997

Gnomad OTH exome AF: 0.992

GnomAD4 exome AF: 0.995 AC: 1387661 AN: 1394330 Hom.: 690623 Cov.: 34 AF XY: 0.995 AC XY: 684496 AN XY: 687660

African (AFR) AF: 0.920 AC: 28971 AN: 31494

American (AMR) AF: 0.992 AC: 35410 AN: 35678

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 25046 AN: 25146

East Asian (EAS) AF: 1.00 AC: 35719 AN: 35722

South Asian (SAS) AF: 0.994 AC: 78598 AN: 79108

European-Finnish (FIN) AF: 1.00 AC: 47411 AN: 47434

Middle Eastern (MID) AF: 0.993 AC: 4113 AN: 4144

European-Non Finnish (NFE) AF: 0.997 AC: 1075075 AN: 1077844

Other (OTH) AF: 0.992 AC: 57318 AN: 57760

GnomAD4 genome AF: 0.978 AC: 144916 AN: 148148 Hom.: 70867 Cov.: 20 AF XY: 0.978 AC XY: 70591 AN XY: 72146

African (AFR) AF: 0.930 AC: 36778 AN: 39548

American (AMR) AF: 0.987 AC: 14776 AN: 14964

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 3437 AN: 3454

East Asian (EAS) AF: 1.00 AC: 4874 AN: 4874

South Asian (SAS) AF: 0.992 AC: 4516 AN: 4552

European-Finnish (FIN) AF: 0.999 AC: 10131 AN: 10138

Middle Eastern (MID) AF: 0.997 AC: 289 AN: 290

European-Non Finnish (NFE) AF: 0.998 AC: 67234 AN: 67400

Other (OTH) AF: 0.977 AC: 1985 AN: 2032

Alfa AF: 0.991 Hom.: 8265

Bravo AF: 0.973

Asia WGS AF: 0.990 AC: 3439 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Familial infantile myasthenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.17
DANN	Benign	0.50
PhyloP100		-3.1
PromoterAI		0.084	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7923716; hg19: chr10-50822226;