7-143292303-A-G

Variant names:

• chr7-143292303-A-G
• NM_032982.4:c.229A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032982.4(CASP2):​c.229A>G​(p.Lys77Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CASP2 NM_032982.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13600135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP2	NM_032982.4	c.229A>G	p.Lys77Glu	missense_variant	Exon 3 of 11	ENST00000310447.10	NP_116764.2
CASP2	NM_001224.5	c.136A>G	p.Lys46Glu	missense_variant	Exon 3 of 12		NP_001215.1
CASP2	NM_032983.4	c.229A>G	p.Lys77Glu	missense_variant	Exon 3 of 10		NP_116765.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP2	ENST00000310447.10	c.229A>G	p.Lys77Glu	missense_variant	Exon 3 of 11	1	NM_032982.4	ENSP00000312664.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000611 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.229A>G (p.K77E) alteration is located in exon 3 (coding exon 3) of the CASP2 gene. This alteration results from a A to G substitution at nucleotide position 229, causing the lysine (K) at amino acid position 77 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T;T;T
Eigen	Benign	-0.087
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;T;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;L;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.79	.;N;N
REVEL	Benign	0.053
Sift	Benign	0.32	.;T;T
Sift4G	Benign	0.090	T;T;D
Polyphen		0.088	.;B;.
Vest4		0.22
MutPred		0.39		Loss of ubiquitination at K77 (P = 0.0098);Loss of ubiquitination at K77 (P = 0.0098);Loss of ubiquitination at K77 (P = 0.0098);
MVP		0.57
MPC		0.63
ClinPred		0.54	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.48

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-142989396;