NM_016302.4:c.654A>T

Variant names:

• chr3-3167667-T-A
• rs373145132
• NM_016302.4:c.654A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016302.4(CRBN):​c.654A>T​(p.Gln218His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q218Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRBN NM_016302.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.879
• Publications: 0 publications found

Genes affected

CRBN (HGNC:30185): (cereblon) This gene encodes a protein related to the Lon protease protein family. In rodents and other mammals this gene product is found in the cytoplasm localized with a calcium channel membrane protein, and is thought to play a role in brain development. Mutations in this gene are associated with autosomal recessive nonsyndromic cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

CRBN Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability, autosomal recessive 2

  Inheritance: AR Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13354275).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016302.4. 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
	CRBN	NM_016302.4	MANE Select	c.654A>T	p.Gln218His	missense	Exon 5 of 11	NP_057386.2
	CRBN	NM_001173482.1		c.651A>T	p.Gln217His	missense	Exon 5 of 11	NP_001166953.1	Q96SW2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRBN	ENST00000231948.9	TSL:1 MANE Select	c.654A>T	p.Gln218His	missense	Exon 5 of 11	ENSP00000231948.4	Q96SW2-1
	CRBN	ENST00000432408.6	TSL:1	c.651A>T	p.Gln217His	missense	Exon 5 of 11	ENSP00000412499.2	Q96SW2-2
	CRBN	ENST00000450014.1	TSL:1	c.639A>T	p.Gln213His	missense	Exon 5 of 5	ENSP00000392073.1	J3QT51

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.70
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.052
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.88
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.11
Sift	Benign	0.12	T
Sift4G	Benign	0.55	T
Polyphen		0.77	P
Vest4		0.26
MutPred		0.42		Gain of glycosylation at S214 (P = 0.0288)
MVP		0.67
MPC		0.081
ClinPred		0.23	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.058
gMVP		0.24
Mutation Taster		=57/43	polymorphism

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: rs373145132; hg19: chr3-3209351;