chr9-26861087-C-G

Variant names:

• chr9-26861087-C-G
• rs764609163
• NM_024828.4:c.718G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024828.4(CAAP1):​c.718G>C​(p.Glu240Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E240K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CAAP1 NM_024828.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.88
• Publications: 0 publications found

Genes affected

CAAP1 (HGNC:25834): (caspase activity and apoptosis inhibitor 1) Involved in negative regulation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24685776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAAP1	NM_024828.4	c.718G>C	p.Glu240Gln	missense_variant	Exon 5 of 6	ENST00000333916.8	NP_079104.3
CAAP1	NM_001167575.2	c.283G>C	p.Glu95Gln	missense_variant	Exon 5 of 6		NP_001161047.1
CAAP1	XM_047423896.1	c.*56G>C		3_prime_UTR_variant	Exon 6 of 6		XP_047279852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAAP1	ENST00000333916.8	c.718G>C	p.Glu240Gln	missense_variant	Exon 5 of 6	1	NM_024828.4	ENSP00000369431.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459034 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 726114

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33334

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109752

Other (OTH) AF: 0.00 AC: 0 AN: 60272

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.029673), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.8	L;.
PhyloP100		3.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.78	N;.
REVEL	Benign	0.11
Sift	Uncertain	0.010	D;.
Sift4G	Benign	0.089	T;T
Polyphen		0.91	P;.
Vest4		0.27
MutPred		0.27		Gain of methylation at K237 (P = 0.0872);.;
MVP		0.31
MPC		0.26
ClinPred		0.75	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.10
Mutation Taster		=91/9	polymorphism

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: rs764609163; hg19: chr9-26861085;