7-143294286-C-G

Variant names:

• chr7-143294286-C-G
• rs4647298
• NM_032982.4:c.532C>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_032982.4(CASP2):​c.532C>G​(p.Pro178Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,611,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: CASP2 NM_032982.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.787

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008542985).
• BP6: Variant 7-143294286-C-G is Benign according to our data. Variant chr7-143294286-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3036802.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP2	NM_032982.4	c.532C>G	p.Pro178Ala	missense_variant	Exon 5 of 11	ENST00000310447.10	NP_116764.2
CASP2	NM_001224.5	c.439C>G	p.Pro147Ala	missense_variant	Exon 5 of 12		NP_001215.1
CASP2	NM_032983.4	c.314C>G	p.Ala105Gly	missense_variant	Exon 4 of 10		NP_116765.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP2	ENST00000310447.10	c.532C>G	p.Pro178Ala	missense_variant	Exon 5 of 11	1	NM_032982.4	ENSP00000312664.5

Frequencies

GnomAD3 genomes AF: 0.000861 AC: 131 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000290 AC: 73 AN: 251398 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135890

Gnomad AFR exome AF: 0.00326

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000147 AC: 215 AN: 1459470 Hom.: 0 Cov.: 30 AF XY: 0.000142 AC XY: 103 AN XY: 726258

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000586

Gnomad4 OTH exome AF: 0.000448

GnomAD4 genome AF: 0.000867 AC: 132 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000900 AC XY: 67 AN XY: 74466

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.00102

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000280 AC: 34

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CASP2-related disorder Benign:1

May 30, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.091
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.0085	T
Sift4G	Pathogenic	0.0	D
Vest4		0.19
MVP		0.71
ClinPred		0.051	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs4647298; hg19: chr7-142991379;