chr10-113729393-C-G

Position:

• chr10-113729393-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001227.5(CASP7):​c.765C>G​(p.Asp255Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,613,424 control chromosomes in the GnomAD database, including 55,528 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.23 (4402 hom., cov: 32)
  • Exomes 𝑓: 0.26 (51126 hom.)
• Consequence: CASP7 NM_001227.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.741

Genes affected

CASP7 (HGNC:1508): (caspase 7) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. The precursor of the encoded protein is cleaved by caspase 3 and 10, is activated upon cell death stimuli and induces apoptosis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011807978).
• BP6: Variant 10-113729393-C-G is Benign according to our data. Variant chr10-113729393-C-G is described in ClinVar as [Benign]. Clinvar id is 1246573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP7	NM_001227.5	c.765C>G	p.Asp255Glu	missense_variant	7/7	ENST00000369318.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP7	ENST00000369318.8	c.765C>G	p.Asp255Glu	missense_variant	7/7	1	NM_001227.5	P1

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35110 AN: 151964 Hom.: 4399 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.412

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.224

GnomAD3 exomes AF: 0.261 AC: 65714 AN: 251392 Hom.: 9012 AF XY: 0.259 AC XY: 35235 AN XY: 135872

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.275

Gnomad ASJ exome AF: 0.194

Gnomad EAS exome AF: 0.422

Gnomad SAS exome AF: 0.238

Gnomad FIN exome AF: 0.277

Gnomad NFE exome AF: 0.258

Gnomad OTH exome AF: 0.258

GnomAD4 exome AF: 0.261 AC: 381044 AN: 1461342 Hom.: 51126 Cov.: 34 AF XY: 0.260 AC XY: 188777 AN XY: 727012

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.277

Gnomad4 ASJ exome AF: 0.196

Gnomad4 EAS exome AF: 0.446

Gnomad4 SAS exome AF: 0.236

Gnomad4 FIN exome AF: 0.274

Gnomad4 NFE exome AF: 0.261

Gnomad4 OTH exome AF: 0.247

GnomAD4 genome AF: 0.231 AC: 35122 AN: 152082 Hom.: 4402 Cov.: 32 AF XY: 0.232 AC XY: 17245 AN XY: 74326

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.238

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.421

Gnomad4 SAS AF: 0.238

Gnomad4 FIN AF: 0.272

Gnomad4 NFE AF: 0.262

Gnomad4 OTH AF: 0.225

Alfa AF: 0.242 Hom.: 3645

Bravo AF: 0.226

TwinsUK AF: 0.242 AC: 896

ALSPAC AF: 0.267 AC: 1029

ESP6500AA AF: 0.145 AC: 638

ESP6500EA AF: 0.253 AC: 2172

ExAC AF: 0.260 AC: 31543

Asia WGS AF: 0.279 AC: 969 AN: 3478

EpiCase AF: 0.251

EpiControl AF: 0.246

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2021	This variant is associated with the following publications: (PMID: 23765963, 19826114) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.5
DANN	Benign	0.50
DEOGEN2	Benign	0.019	T;T;T;T;T;.;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.73	T;.;T;.;.;T;T
MetaRNN	Benign	0.0012	T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.96	.;N;.;N;N;.;N
REVEL	Benign	0.15
Sift	Benign	0.84	.;T;.;T;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;B;B;.
Vest4		0.0060
MutPred		0.11		Gain of disorder (P = 0.0902);Gain of disorder (P = 0.0902);.;Gain of disorder (P = 0.0902);Gain of disorder (P = 0.0902);.;.;
MPC		0.14
ClinPred		0.0019	T
GERP RS		1.7
Varity_R		0.12
gMVP		0.28

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: rs2227310; hg19: chr10-115489152; COSMIC: COSV61881355; COSMIC: COSV61881355;