rs7636

Variant names:

• chr7-100892456-G-A
• rs7636
• NM_000665.5:c.1431C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-100892456-G-A
• chr7-100892456-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000665.5(ACHE):​c.1431C>T​(p.Pro477Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0514 in 1,559,426 control chromosomes in the GnomAD database, including 3,938 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.10 (1412 hom., cov: 30)
  • Exomes 𝑓: 0.046 (2526 hom.)
• Consequence: ACHE NM_000665.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0170
• Publications: 40 publications found

Genes affected

ACHE (HGNC:108): (acetylcholinesterase (Yt blood group)) Acetylcholinesterase hydrolyzes the neurotransmitter, acetylcholine at neuromuscular junctions and brain cholinergic synapses, and thus terminates signal transmission. It is also found on the red blood cell membranes, where it constitutes the Yt blood group antigen. Acetylcholinesterase exists in multiple molecular forms which possess similar catalytic properties, but differ in their oligomeric assembly and mode of cell attachment to the cell surface. It is encoded by the single ACHE gene, and the structural diversity in the gene products arises from alternative mRNA splicing, and post-translational associations of catalytic and structural subunits. The major form of acetylcholinesterase found in brain, muscle and other tissues is the hydrophilic species, which forms disulfide-linked oligomers with collagenous, or lipid-containing structural subunits. The other, alternatively spliced form, expressed primarily in the erythroid tissues, differs at the C-terminal end, and contains a cleavable hydrophobic peptide with a GPI-anchor site. It associates with the membranes through the phosphoinositide (PI) moieties added post-translationally. AChE activity may constitute a sensitive biomarker of RBC ageing in vivo, and thus, may be of aid in understanding the effects of transfusion[provided by RefSeq, Sep 2019]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000665.5. 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
	ACHE	NM_000665.5	MANE Select	c.1431C>T	p.Pro477Pro	synonymous	Exon 3 of 5	NP_000656.1	P22303-1
	ACHE	NM_001367918.1		c.1632C>T	p.Pro544Pro	synonymous	Exon 3 of 5	NP_001354847.1
	ACHE	NM_001367919.2		c.1629C>T	p.Pro543Pro	synonymous	Exon 3 of 5	NP_001354848.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACHE	ENST00000241069.11	TSL:1 MANE Select	c.1431C>T	p.Pro477Pro	synonymous	Exon 3 of 5	ENSP00000241069.5	P22303-1
	ACHE	ENST00000302913.8	TSL:1	c.1431C>T	p.Pro477Pro	synonymous	Exon 3 of 5	ENSP00000303211.4	P22303-2
	ACHE	ENST00000411582.4	TSL:1	c.1431C>T	p.Pro477Pro	synonymous	Exon 3 of 5	ENSP00000404865.1	P22303-2

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15232 AN: 149882 Hom.: 1409 Cov.: 30

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.00776

Gnomad AMR AF: 0.0661

Gnomad ASJ AF: 0.0879

Gnomad EAS AF: 0.000588

Gnomad SAS AF: 0.0630

Gnomad FIN AF: 0.0288

Gnomad MID AF: 0.103

Gnomad NFE AF: 0.0460

Gnomad OTH AF: 0.106

GnomAD2 exomes AF: 0.0580 AC: 13155 AN: 226680 AF XY: 0.0568

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.0400

Gnomad ASJ exome AF: 0.0837

Gnomad EAS exome AF: 0.000339

Gnomad FIN exome AF: 0.0294

Gnomad NFE exome AF: 0.0469

Gnomad OTH exome AF: 0.0603

GnomAD4 exome AF: 0.0460 AC: 64903 AN: 1409426 Hom.: 2526 Cov.: 31 AF XY: 0.0469 AC XY: 32537 AN XY: 693058

African (AFR) AF: 0.251 AC: 8057 AN: 32134

American (AMR) AF: 0.0456 AC: 1830 AN: 40114

Ashkenazi Jewish (ASJ) AF: 0.0845 AC: 1988 AN: 23518

East Asian (EAS) AF: 0.000284 AC: 11 AN: 38774

South Asian (SAS) AF: 0.0616 AC: 4954 AN: 80486

European-Finnish (FIN) AF: 0.0290 AC: 1506 AN: 51972

Middle Eastern (MID) AF: 0.115 AC: 637 AN: 5520

European-Non Finnish (NFE) AF: 0.0394 AC: 42556 AN: 1078922

Other (OTH) AF: 0.0580 AC: 3364 AN: 57986

GnomAD4 genome AF: 0.102 AC: 15265 AN: 150000 Hom.: 1412 Cov.: 30 AF XY: 0.0995 AC XY: 7279 AN XY: 73170

African (AFR) AF: 0.247 AC: 10020 AN: 40604

American (AMR) AF: 0.0657 AC: 984 AN: 14976

Ashkenazi Jewish (ASJ) AF: 0.0879 AC: 304 AN: 3460

East Asian (EAS) AF: 0.000589 AC: 3 AN: 5090

South Asian (SAS) AF: 0.0627 AC: 295 AN: 4708

European-Finnish (FIN) AF: 0.0288 AC: 299 AN: 10376

Middle Eastern (MID) AF: 0.104 AC: 30 AN: 288

European-Non Finnish (NFE) AF: 0.0460 AC: 3109 AN: 67554

Other (OTH) AF: 0.105 AC: 214 AN: 2042

Alfa AF: 0.0619 Hom.: 2166

Bravo AF: 0.110

Asia WGS AF: 0.0420 AC: 144 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.90
PhyloP100		0.017
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: rs7636; hg19: chr7-100490077; COSMIC: COSV53817532; COSMIC: COSV53817532;