chr7-143299968-C-G

Variant names:

• chr7-143299968-C-G
• rs150852779
• NM_032982.4:c.793C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_032982.4(CASP2):​c.793C>G​(p.Arg265Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000272 in 1,614,124 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: CASP2 NM_032982.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.46
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.051181257).
• BP6: Variant 7-143299968-C-G is Benign according to our data. Variant chr7-143299968-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2658111.

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.793C>G	p.Arg265Gly	missense	Exon 7 of 11	NP_116764.2
	CASP2	NM_001224.5		c.700C>G	p.Arg234Gly	missense	Exon 7 of 12	NP_001215.1
	CASP2	NM_032983.4		c.*248C>G		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.793C>G	p.Arg265Gly	missense	Exon 7 of 11	ENSP00000312664.5	P42575-1
	CASP2	ENST00000619992.4	TSL:1	c.*248C>G		3_prime_UTR	Exon 6 of 10	ENSP00000481929.1	A0A087WYM1
	CASP2	ENST00000350623.7	TSL:1	n.*248C>G		non_coding_transcript_exon	Exon 6 of 10	ENSP00000340030.3	A0A087WYM1

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000298 AC: 75 AN: 251484 AF XY: 0.000294

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000225 AC: 329 AN: 1461862 Hom.: 1 Cov.: 32 AF XY: 0.000223 AC XY: 162 AN XY: 727230

African (AFR) AF: 0.00266 AC: 89 AN: 33478

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.000168 AC: 187 AN: 1111994

Other (OTH) AF: 0.000397 AC: 24 AN: 60390

GnomAD4 genome AF: 0.000722 AC: 110 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000819 AC XY: 61 AN XY: 74444

African (AFR) AF: 0.00212 AC: 88 AN: 41548

American (AMR) AF: 0.000654 AC: 10 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68020

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000157 Hom.: 0

Bravo AF: 0.000876

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.045
Sift	Uncertain	0.022	D
Sift4G	Benign	0.27	T
Polyphen		0.93	P
Vest4		0.49
MVP		0.65
MPC		0.94
ClinPred		0.018	T
GERP RS		4.5
Varity_R		0.49
gMVP		0.49
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: rs150852779; hg19: chr7-142997061;