NM_020371.3:c.196C>T

Variant names:

• chr15-34038851-G-A
• rs1426801522
• NM_020371.3:c.196C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020371.3(AVEN):​c.196C>T​(p.Arg66*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000985 in 1,015,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.9e-7 (0 hom.)
• Consequence: AVEN NM_020371.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0670
• Publications: 0 publications found

Genes affected

AVEN (HGNC:13509): (apoptosis and caspase activation inhibitor) Involved in negative regulation of apoptotic process. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

CHRM5 (HGNC:1954): (cholinergic receptor muscarinic 5) The muscarinic cholinergic receptors belong to a larger family of G protein-coupled receptors. The functional diversity of these receptors is defined by the binding of acetylcholine and includes cellular responses such as adenylate cyclase inhibition, phosphoinositide degeneration, and potassium channel mediation. Muscarinic receptors influence many effects of acetylcholine in the central and peripheral nervous system. The clinical implications of this receptor are unknown; however, stimulation of this receptor is known to increase cyclic AMP levels. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020371.3. 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
	AVEN	NM_020371.3	MANE Select	c.196C>T	p.Arg66*	stop_gained	Exon 1 of 6	NP_065104.1	Q9NQS1
	CHRM5	NM_012125.4	MANE Select	c.-407-7689G>A		intron	N/A	NP_036257.1	P08912
	CHRM5	NM_001320917.2		c.-75-23792G>A		intron	N/A	NP_001307846.1	P08912

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AVEN	ENST00000306730.8	TSL:1 MANE Select	c.196C>T	p.Arg66*	stop_gained	Exon 1 of 6	ENSP00000306822.3	Q9NQS1
	CHRM5	ENST00000383263.7	TSL:2 MANE Select	c.-407-7689G>A		intron	N/A	ENSP00000372750.5	P08912
	CHRM5	ENST00000557872.1	TSL:1	c.-76+20386G>A		intron	N/A	ENSP00000453745.1	P08912

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.85e-7 AC: 1 AN: 1015076 Hom.: 0 Cov.: 29 AF XY: 0.00000207 AC XY: 1 AN XY: 482174

African (AFR) AF: 0.00 AC: 0 AN: 19552

American (AMR) AF: 0.00 AC: 0 AN: 6656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10746

East Asian (EAS) AF: 0.00 AC: 0 AN: 18812

South Asian (SAS) AF: 0.00 AC: 0 AN: 20584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2498

European-Non Finnish (NFE) AF: 0.00000113 AC: 1 AN: 881072

Other (OTH) AF: 0.00 AC: 0 AN: 38022

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.49	N
PhyloP100		-0.067
Vest4		0.33
GERP RS		2.1
PromoterAI		-0.22	Neutral
Mutation Taster		=15/185	disease causing (fs/PTC)

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: rs1426801522; hg19: chr15-34331052;