10-113697505-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001227.5(CASP7):c.12T>G(p.Asp4Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,607,744 control chromosomes in the GnomAD database, including 8,730 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (860 hom., cov: 32)
  • Exomes 𝑓: 0.10 (7870 hom.)
• Consequence: CASP7 NM_001227.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00100

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017143488).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP7	NM_001227.5	c.12T>G	p.Asp4Glu	missense_variant	2/7	ENST00000369318.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP7	ENST00000369318.8	c.12T>G	p.Asp4Glu	missense_variant	2/7	1	NM_001227.5	P1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16098 AN: 152042 Hom.: 858 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0961

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.0885

Gnomad SAS AF: 0.0926

Gnomad FIN AF: 0.0692

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.123

GnomAD3 exomes AF: 0.0952 AC: 23929 AN: 251318 Hom.: 1232 AF XY: 0.0969 AC XY: 13165 AN XY: 135818

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.0646

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.0908

Gnomad SAS exome AF: 0.0993

Gnomad FIN exome AF: 0.0719

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.101 AC: 146821 AN: 1455584 Hom.: 7870 Cov.: 30 AF XY: 0.101 AC XY: 73398 AN XY: 724428

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.0669

Gnomad4 ASJ exome AF: 0.116

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.101

Gnomad4 FIN exome AF: 0.0695

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.108

GnomAD4 genome AF: 0.106 AC: 16111 AN: 152160 Hom.: 860 Cov.: 32 AF XY: 0.104 AC XY: 7741 AN XY: 74416

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.0959

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.0889

Gnomad4 SAS AF: 0.0929

Gnomad4 FIN AF: 0.0692

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.122

Alfa AF: 0.102 Hom.: 1586

Bravo AF: 0.106

TwinsUK AF: 0.103 AC: 383

ALSPAC AF: 0.101 AC: 389

ESP6500AA AF: 0.123 AC: 542

ESP6500EA AF: 0.104 AC: 892

ExAC AF: 0.0970 AC: 11780

Asia WGS AF: 0.106 AC: 366 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.103

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	4.5
Dann	Benign	0.97
DEOGEN2	Benign	0.042	T;T;.;T;.;T;T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.49	T;T;.;.;T;.;.;T
MetaRNN	Benign	0.0017	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.;M;M;M;M;M;.
MutationTaster	Benign	1.0	P;P;P;P;P;P
Sift4G	Benign	0.33	T;T;D;T;D;T;T;T
Polyphen		0.15	B;.;P;B;P;B;B;B
Vest4		0.17
MutPred		0.095		Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);.;
ClinPred		0.0039	T
GERP RS		2.0
Varity_R		0.047

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: rs11555408; hg19: chr10-115457264; COSMIC: COSV61881934;