3-3172760-A-G

Variant names:

• chr3-3172760-A-G
• rs530596639
• NM_016302.4:c.527+16T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_016302.4(CRBN):​c.527+16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,608,268 control chromosomes in the GnomAD database, including 5 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 0.000053 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (4 hom.)
• Consequence: CRBN NM_016302.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0600
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000525 (8/152356) while in subpopulation SAS AF = 0.00145 (7/4828). AF 95% confidence interval is 0.00068. There are 1 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.527+16T>C		intron	N/A	NP_057386.2
	CRBN	NM_001173482.1		c.524+16T>C		intron	N/A	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.527+16T>C		intron	N/A	ENSP00000231948.4	Q96SW2-1
	CRBN	ENST00000432408.6	TSL:1	c.524+16T>C		intron	N/A	ENSP00000412499.2	Q96SW2-2
	CRBN	ENST00000450014.1	TSL:1	c.512+16T>C		intron	N/A	ENSP00000392073.1	J3QT51

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152238 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000350 AC: 88 AN: 251252 AF XY: 0.000471

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000159 AC: 231 AN: 1455912 Hom.: 4 Cov.: 28 AF XY: 0.000232 AC XY: 168 AN XY: 724788

African (AFR) AF: 0.00 AC: 0 AN: 33348

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.00245 AC: 211 AN: 86124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5754

European-Non Finnish (NFE) AF: 0.00000723 AC: 8 AN: 1106654

Other (OTH) AF: 0.000150 AC: 9 AN: 60194

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152356 Hom.: 1 Cov.: 33 AF XY: 0.0000939 AC XY: 7 AN XY: 74510

African (AFR) AF: 0.00 AC: 0 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.3
DANN	Benign	0.85
PhyloP100		-0.060
Mutation Taster		=100/0	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: rs530596639; hg19: chr3-3214444;