rs61144803

Variant names:

• chr12-93841389-A-G
• rs61144803
• NM_003805.5:c.299-8581A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003805.5(CRADD):​c.299-8581A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0407 in 152,256 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.041 (156 hom., cov: 32)
• Consequence: CRADD NM_003805.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0540
• Publications: 12 publications found

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]

CRADD Gene-Disease associations (from GenCC):

• syndromic intellectual disability

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal recessive 34

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRADD	NM_003805.5	c.299-8581A>G		intron_variant	Intron 2 of 2	ENST00000332896.8	NP_003796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRADD	ENST00000332896.8	c.299-8581A>G		intron_variant	Intron 2 of 2	1	NM_003805.5	ENSP00000327647.3

Frequencies

GnomAD3 genomes AF: 0.0407 AC: 6192 AN: 152138 Hom.: 155 Cov.: 32

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0774

Gnomad ASJ AF: 0.0513

Gnomad EAS AF: 0.0304

Gnomad SAS AF: 0.0608

Gnomad FIN AF: 0.0495

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0388

Gnomad OTH AF: 0.0425

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0407 AC: 6201 AN: 152256 Hom.: 156 Cov.: 32 AF XY: 0.0422 AC XY: 3144 AN XY: 74444

African (AFR) AF: 0.0265 AC: 1099 AN: 41534

American (AMR) AF: 0.0778 AC: 1190 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0513 AC: 178 AN: 3468

East Asian (EAS) AF: 0.0305 AC: 158 AN: 5186

South Asian (SAS) AF: 0.0611 AC: 295 AN: 4828

European-Finnish (FIN) AF: 0.0495 AC: 524 AN: 10596

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0388 AC: 2639 AN: 68028

Other (OTH) AF: 0.0421 AC: 89 AN: 2114

Alfa AF: 0.0404 Hom.: 231

Bravo AF: 0.0416

Asia WGS AF: 0.0510 AC: 178 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.58
PhyloP100		0.054
Mutation Taster		=100/0	polymorphism (auto)

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: rs61144803; hg19: chr12-94235165;