12-93864420-T-C

Variant names:

• chr12-93864420-T-C
• rs4275668
• NM_001320100.2:c.299-29630T>C

Variant summary

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

The NM_001320100.2(CRADD):​c.299-29630T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 152,080 control chromosomes in the GnomAD database, including 11,546 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 0.37 (11546 hom., cov: 32)
• Consequence: CRADD NM_001320100.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0740
• 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, 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320100.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRADD	NM_001320100.2		c.299-29630T>C		intron	N/A	NP_001307029.1	F5H7C2
	CRADD	NR_135147.2		n.526+4978T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRADD	ENST00000548483.5	TSL:2	c.299-29630T>C		intron	N/A	ENSP00000448685.1	F5H7C2
	CRADD	ENST00000551065.5	TSL:2	n.*110+4978T>C		intron	N/A	ENSP00000448425.1	P78560-2

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56804 AN: 151962 Hom.: 11545 Cov.: 32

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.371

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

GnomAD4 genome AF: 0.374 AC: 56832 AN: 152080 Hom.: 11546 Cov.: 32 AF XY: 0.370 AC XY: 27531 AN XY: 74356

African (AFR) AF: 0.227 AC: 9418 AN: 41484

American (AMR) AF: 0.339 AC: 5180 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1855 AN: 3472

East Asian (EAS) AF: 0.333 AC: 1723 AN: 5178

South Asian (SAS) AF: 0.362 AC: 1749 AN: 4828

European-Finnish (FIN) AF: 0.391 AC: 4128 AN: 10560

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.464 AC: 31549 AN: 67972

Other (OTH) AF: 0.373 AC: 786 AN: 2110

Alfa AF: 0.432 Hom.: 26153

Bravo AF: 0.361

Asia WGS AF: 0.339 AC: 1180 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.8
DANN	Benign	0.55
PhyloP100		-0.074
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4275668;

hg19: chr12-94258196;