12-98662518-G-C

Variant names:

• chr12-98662518-G-C
• NM_181861.2:c.773G>C
• APAF1 p.Cys258Ser

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_181861.2(APAF1):​c.773G>C​(p.Cys258Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APAF1 NM_181861.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.25
• Publications: 0 publications found

Genes affected

APAF1 (HGNC:576): (apoptotic peptidase activating factor 1) This gene encodes a cytoplasmic protein that initiates apoptosis. This protein contains several copies of the WD-40 domain, a caspase recruitment domain (CARD), and an ATPase domain (NB-ARC). Upon binding cytochrome c and dATP, this protein forms an oligomeric apoptosome. The apoptosome binds and cleaves caspase 9 preproprotein, releasing its mature, activated form. Activated caspase 9 stimulates the subsequent caspase cascade that commits the cell to apoptosis. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

APAF1 Gene-Disease associations (from GenCC):

• depressive disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40210986).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181861.2. 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
	APAF1	NM_181861.2	MANE Select	c.773G>C	p.Cys258Ser	missense	Exon 6 of 27	NP_863651.1	O14727-1
	APAF1	NM_013229.3		c.740G>C	p.Cys247Ser	missense	Exon 6 of 27	NP_037361.1	O14727-2
	APAF1	NM_181868.2		c.773G>C	p.Cys258Ser	missense	Exon 6 of 26	NP_863658.1	O14727-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APAF1	ENST00000551964.6	TSL:1 MANE Select	c.773G>C	p.Cys258Ser	missense	Exon 6 of 27	ENSP00000448165.2	O14727-1
	APAF1	ENST00000550527.5	TSL:1	c.740G>C	p.Cys247Ser	missense	Exon 5 of 26	ENSP00000448449.1	O14727-2
	APAF1	ENST00000547045.5	TSL:1	c.773G>C	p.Cys258Ser	missense	Exon 5 of 25	ENSP00000449791.1	O14727-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.2	L
PhyloP100		5.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.020	D
Sift4G	Benign	0.19	T
Varity_R		0.64
gMVP		0.75
Mutation Taster		=72/28	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-99056296;