7-143299989-G-T

Variant names:

• chr7-143299989-G-T
• rs370097426
• NM_032982.4:c.814G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032982.4(CASP2):​c.814G>T​(p.Val272Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. V272M) 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: 5.14
• Publications: 2 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

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.814G>T	p.Val272Leu	missense	Exon 7 of 11	NP_116764.2
	CASP2	NM_001224.5		c.721G>T	p.Val241Leu	missense	Exon 7 of 12	NP_001215.1
	CASP2	NM_032983.4		c.*269G>T		3_prime_UTR	Exon 6 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.814G>T	p.Val272Leu	missense	Exon 7 of 11	ENSP00000312664.5	P42575-1
	CASP2	ENST00000619992.4	TSL:1	c.*269G>T		3_prime_UTR	Exon 6 of 10	ENSP00000481929.1	A0A087WYM1
	CASP2	ENST00000350623.7	TSL:1	n.*269G>T		non_coding_transcript_exon	Exon 6 of 10	ENSP00000340030.3	A0A087WYM1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.18
Sift	Benign	0.10	T
Sift4G	Benign	0.22	T
Polyphen		1.0	D
Vest4		0.60
MutPred		0.68		Loss of sheet (P = 0.1398)
MVP		0.71
MPC		1.1
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.37
gMVP		0.63
Mutation Taster		=64/36	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: rs370097426; hg19: chr7-142997082; COSMIC: COSV100130967; COSMIC: COSV100130967;