7-143291550-G-A

Variant names:

• chr7-143291550-G-A
• rs774249957
• NM_032982.4:c.85G>A

Variant summary

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

The NM_001224.5(CASP2):​c.-9G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CASP2 NM_001224.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35

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=0.1501073).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP2	NM_032982.4	c.85G>A	p.Val29Met	missense_variant	Exon 2 of 11	ENST00000310447.10	NP_116764.2
CASP2	NM_001224.5	c.-9G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 12		NP_001215.1
CASP2	NM_032983.4	c.85G>A	p.Val29Met	missense_variant	Exon 2 of 10		NP_116765.2
CASP2	NM_001224.5	c.-9G>A		5_prime_UTR_variant	Exon 2 of 12		NP_001215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP2	ENST00000310447.10	c.85G>A	p.Val29Met	missense_variant	Exon 2 of 11	1	NM_032982.4	ENSP00000312664.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251486 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461818 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727216

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.85G>A (p.V29M) alteration is located in exon 2 (coding exon 2) of the CASP2 gene. This alteration results from a G to A substitution at nucleotide position 85, causing the valine (V) at amino acid position 29 to be replaced by a methionine (M). 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	0.097
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T;T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.096	N
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;L;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.34	.;N;N
REVEL	Benign	0.045
Sift	Benign	0.095	.;T;D
Sift4G	Benign	0.13	T;T;T
Polyphen		0.048	.;B;.
Vest4		0.12
MutPred		0.44		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.64
MPC		0.39
ClinPred		0.087	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.040
gMVP		0.27

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: rs774249957; hg19: chr7-142988643;