rs9668896

Variant names:

• chr12-93677236-C-T
• rs9668896
• NM_003805.5:c.-243C>T

Variant summary

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

The NM_003805.5(CRADD):​c.-243C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0618 in 152,248 control chromosomes in the GnomAD database, including 408 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 0.062 (408 hom., cov: 32)
  • Exomes 𝑓: 0.14 (0 hom.)
• Consequence: CRADD NM_003805.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.43
• Publications: 7 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=-0.64).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRADD	NM_003805.5	c.-243C>T		upstream_gene_variant		ENST00000332896.8	NP_003796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRADD	ENST00000332896.8	c.-243C>T		upstream_gene_variant		1	NM_003805.5	ENSP00000327647.3

Frequencies

GnomAD3 genomes AF: 0.0616 AC: 9374 AN: 152118 Hom.: 402 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0390

Gnomad ASJ AF: 0.0824

Gnomad EAS AF: 0.0985

Gnomad SAS AF: 0.0886

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0347

Gnomad OTH AF: 0.0511

GnomAD4 exome AF: 0.143 AC: 2 AN: 14 Hom.: 0 AF XY: 0.125 AC XY: 1 AN XY: 8

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.167 AC: 1 AN: 6

Other (OTH) AF: 0.00 AC: 0 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0618 AC: 9409 AN: 152234 Hom.: 408 Cov.: 32 AF XY: 0.0608 AC XY: 4526 AN XY: 74446

African (AFR) AF: 0.117 AC: 4863 AN: 41530

American (AMR) AF: 0.0390 AC: 596 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0824 AC: 286 AN: 3472

East Asian (EAS) AF: 0.0989 AC: 512 AN: 5176

South Asian (SAS) AF: 0.0885 AC: 427 AN: 4824

European-Finnish (FIN) AF: 0.0200 AC: 212 AN: 10610

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0347 AC: 2357 AN: 68008

Other (OTH) AF: 0.0521 AC: 110 AN: 2112

Alfa AF: 0.0448 Hom.: 250

Bravo AF: 0.0647

Asia WGS AF: 0.0800 AC: 276 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.19
DANN	Benign	0.87
PhyloP100		-1.4
PromoterAI		-0.024	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9668896; hg19: chr12-94071012;