rs76014951

Variant names:

• chr10-49648597-C-T
• rs76014951
• NM_020549.5:c.1372C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020549.5(CHAT):​c.1372C>T​(p.Leu458Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00511 in 1,611,882 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (26 hom.)
• Consequence: CHAT NM_020549.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.91
• 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: 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 (MetaRNN=0.013102263).
• BP6: Variant 10-49648597-C-T is Benign according to our data. Variant chr10-49648597-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 199158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00367 (559/152292) while in subpopulation NFE AF = 0.00523 (356/68028). AF 95% confidence interval is 0.00478. There are 3 homozygotes in GnomAd4. There are 302 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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.1372C>T	p.Leu458Phe	missense	Exon 9 of 15	NP_065574.4	P28329-1
	CHAT	NM_001142933.2		c.1126C>T	p.Leu376Phe	missense	Exon 10 of 16	NP_001136405.2	P28329-2
	CHAT	NM_001142929.2		c.1018C>T	p.Leu340Phe	missense	Exon 9 of 15	NP_001136401.2	P28329-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	ENST00000337653.7	TSL:1 MANE Select	c.1372C>T	p.Leu458Phe	missense	Exon 9 of 15	ENSP00000337103.2	P28329-1
	CHAT	ENST00000395562.2	TSL:1	c.1126C>T	p.Leu376Phe	missense	Exon 10 of 16	ENSP00000378929.2	P28329-2
	CHAT	ENST00000339797.5	TSL:1	c.1018C>T	p.Leu340Phe	missense	Exon 9 of 15	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes AF: 0.00367 AC: 559 AN: 152174 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00523

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00388 AC: 967 AN: 249232 AF XY: 0.00372

Gnomad AFR exome AF: 0.000808

Gnomad AMR exome AF: 0.000958

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0150

Gnomad NFE exome AF: 0.00505

Gnomad OTH exome AF: 0.00477

GnomAD4 exome AF: 0.00527 AC: 7685 AN: 1459590 Hom.: 26 Cov.: 31 AF XY: 0.00504 AC XY: 3659 AN XY: 726158

African (AFR) AF: 0.000598 AC: 20 AN: 33444

American (AMR) AF: 0.000917 AC: 41 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86026

European-Finnish (FIN) AF: 0.0131 AC: 696 AN: 53288

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5760

European-Non Finnish (NFE) AF: 0.00594 AC: 6597 AN: 1110256

Other (OTH) AF: 0.00507 AC: 306 AN: 60314

GnomAD4 genome AF: 0.00367 AC: 559 AN: 152292 Hom.: 3 Cov.: 32 AF XY: 0.00406 AC XY: 302 AN XY: 74462

African (AFR) AF: 0.00113 AC: 47 AN: 41556

American (AMR) AF: 0.000980 AC: 15 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0130 AC: 138 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00523 AC: 356 AN: 68028

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00474 Hom.: 9

Bravo AF: 0.00271

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00365 AC: 443

EpiCase AF: 0.00442

EpiControl AF: 0.00541

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.83
Sift	Benign	0.070	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.77
MVP		0.97
MPC		0.93
ClinPred		0.014	T
GERP RS		5.0
Varity_R		0.69
gMVP		0.67
Mutation Taster		=95/5	polymorphism

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: rs76014951; hg19: chr10-50856643;