rs12308959

Positions:

• chr12-93842070-G-A
• chr12-93842070-G-C
• chr12-93842070-G-T

Variant summary

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

The NM_003805.5(CRADD):​c.299-7900G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 151,964 control chromosomes in the GnomAD database, including 16,334 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 0.46 (16334 hom., cov: 32)
• Consequence: CRADD NM_003805.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.651

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRADD	NM_003805.5	c.299-7900G>A		intron_variant		ENST00000332896.8	NP_003796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRADD	ENST00000332896.8	c.299-7900G>A		intron_variant		1	NM_003805.5	ENSP00000327647	P1

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69840 AN: 151846 Hom.: 16319 Cov.: 32

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.472

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

GnomAD4 genome AF: 0.460 AC: 69888 AN: 151964 Hom.: 16334 Cov.: 32 AF XY: 0.458 AC XY: 33996 AN XY: 74300

Gnomad4 AFR AF: 0.458

Gnomad4 AMR AF: 0.432

Gnomad4 ASJ AF: 0.453

Gnomad4 EAS AF: 0.683

Gnomad4 SAS AF: 0.409

Gnomad4 FIN AF: 0.403

Gnomad4 NFE AF: 0.462

Gnomad4 OTH AF: 0.477

Alfa AF: 0.456 Hom.: 10317

Bravo AF: 0.463

Asia WGS AF: 0.550 AC: 1913 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	1.1
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs12308959; hg19: chr12-94235846;