7-143288526-G-C

Variant names:

• chr7-143288526-G-C
• rs368981317
• NM_032982.4:c.71G>C

Variant summary

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

The NM_032982.4(CASP2):​c.71G>C​(p.Arg24Pro) 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. 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. R24L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASP2 NM_032982.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.26
• Publications: 1 publications found

Genes affected

CASP2 (HGNC:1503): (caspase 2) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Caspases mediate cellular apoptosis through the proteolytic cleavage of specific protein substrates. The encoded protein may function in stress-induced cell death pathways, cell cycle maintenance, and the suppression of tumorigenesis. Increased expression of this gene may play a role in neurodegenerative disorders including Alzheimer's disease, Huntington's disease and temporal lobe epilepsy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

CASP2 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: G2P, 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=0.36768478).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032982.4. 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
	CASP2	NM_032982.4	MANE Select	c.71G>C	p.Arg24Pro	missense	Exon 1 of 11	NP_116764.2
	CASP2	NM_032983.4		c.71G>C	p.Arg24Pro	missense	Exon 1 of 10	NP_116765.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP2	ENST00000310447.10	TSL:1 MANE Select	c.71G>C	p.Arg24Pro	missense	Exon 1 of 11	ENSP00000312664.5	P42575-1
	CASP2	ENST00000619992.4	TSL:1	c.71G>C	p.Arg24Pro	missense	Exon 1 of 10	ENSP00000481929.1	A0A087WYM1
	CASP2	ENST00000350623.7	TSL:1	n.71G>C		non_coding_transcript_exon	Exon 1 of 10	ENSP00000340030.3	A0A087WYM1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T
Eigen	Benign	0.0050
Eigen_PC	Benign	0.055
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PhyloP100		4.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.15
Sift	Benign	0.067	T
Sift4G	Uncertain	0.043	D
Polyphen		0.61	P
Vest4		0.41
MutPred		0.57		Loss of MoRF binding (P = 0.007)
MVP		0.83
MPC		0.86
ClinPred		0.94	D
GERP RS		4.3
PromoterAI		-0.022	Neutral
Varity_R		0.29
gMVP		0.43
Mutation Taster		=77/23	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: rs368981317; hg19: chr7-142985619;