12-93678925-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003805.5(CRADD):c.151C>A(p.Leu51Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,614,164 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (9 hom.)
• Consequence: CRADD NM_003805.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.03

Genes affected

CRADD (HGNC:2340): (CASP2 and RIPK1 domain containing adaptor with death domain) This gene encodes a protein containing a death domain (DD) motif. This protein recruits caspase 2/ICH1 to the cell death signal transduction complex, which includes tumor necrosis factor receptor 1 (TNFR1A) and RIPK1/RIP kinase, and acts in promoting apoptosis. A mutation in this gene was associated with cognitive disability. A related pseudogene is found on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007781446).
• BP6: Variant 12-93678925-C-A is Benign according to our data. Variant chr12-93678925-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 784526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-93678925-C-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRADD	NM_003805.5	c.151C>A	p.Leu51Ile	missense_variant	2/3	ENST00000332896.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRADD	ENST00000332896.8	c.151C>A	p.Leu51Ile	missense_variant	2/3	1	NM_003805.5	P1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00127 AC: 319 AN: 251484 Hom.: 3 AF XY: 0.00150 AC XY: 204 AN XY: 135922

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00346

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00143 AC: 2097 AN: 1461876 Hom.: 9 Cov.: 31 AF XY: 0.00151 AC XY: 1099 AN XY: 727240

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00345

Gnomad4 FIN exome AF: 0.000505

Gnomad4 NFE exome AF: 0.00150

Gnomad4 OTH exome AF: 0.000811

GnomAD4 genome AF: 0.00100 AC: 153 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000886 AC XY: 66 AN XY: 74470

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00161 Hom.: 2

Bravo AF: 0.00114

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00121 AC: 147

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00154

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	CRADD: BP4, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 16, 2020

- -

CRADD-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2022

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	0.15
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.042	T;T;.;T;T
Eigen	Benign	-0.042
Eigen_PC	Benign	0.065
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.88	D;.;D;D;D
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.0078	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.72	N;N;N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.64	N;N;N;N;N
REVEL	Benign	0.019
Sift	Benign	0.20	T;T;T;T;T
Sift4G	Benign	0.10	T;T;T;T;T
Polyphen		0.045, 0.95	.;B;.;P;B
Vest4		0.22
MVP		0.24
MPC		0.13
ClinPred		0.016	T
GERP RS		4.3
Varity_R		0.20
gMVP		0.14

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: rs4332566; hg19: chr12-94072701; COSMIC: COSV105194651;