rs200333487

Variant names:

• chr8-116854479-A-G
• rs200333487
• NM_006265.3:c.938-11T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006265.3(RAD21):​c.938-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0053 in 1,595,000 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (31 hom.)
• Consequence: RAD21 NM_006265.3 intron
• Scores: Splicing: ADA: 0.001232
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.71
• Publications: 0 publications found

Genes affected

RAD21 (HGNC:9811): (RAD21 cohesin complex component) The protein encoded by this gene is highly similar to the gene product of Schizosaccharomyces pombe rad21, a gene involved in the repair of DNA double-strand breaks, as well as in chromatid cohesion during mitosis. This protein is a nuclear phospho-protein, which becomes hyperphosphorylated in cell cycle M phase. The highly regulated association of this protein with mitotic chromatin specifically at the centromere region suggests its role in sister chromatid cohesion in mitotic cells. [provided by RefSeq, Jul 2008]

RAD21 Gene-Disease associations (from GenCC):

• Cornelia de Lange syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Cornelia de Lange syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Mungan syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 8-116854479-A-G is Benign according to our data. Variant chr8-116854479-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00397 (605/152248) while in subpopulation NFE AF = 0.00763 (519/68006). AF 95% confidence interval is 0.00709. There are 3 homozygotes in GnomAd4. There are 256 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 605 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006265.3. 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
	RAD21	NM_006265.3	MANE Select	c.938-11T>C		intron	N/A	NP_006256.1	O60216

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD21	ENST00000297338.7	TSL:1 MANE Select	c.938-11T>C		intron	N/A	ENSP00000297338.2	O60216
	RAD21	ENST00000517749.2	TSL:1	c.938-11T>C		intron	N/A	ENSP00000430273.2	O60216
	RAD21	ENST00000517485.6	TSL:3	c.938-11T>C		intron	N/A	ENSP00000427923.2	O60216

Frequencies

GnomAD3 genomes AF: 0.00398 AC: 605 AN: 152132 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00763

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00373 AC: 932 AN: 249888 AF XY: 0.00357

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.000961

Gnomad ASJ exome AF: 0.00481

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00279

Gnomad NFE exome AF: 0.00677

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00544 AC: 7847 AN: 1442752 Hom.: 31 Cov.: 29 AF XY: 0.00529 AC XY: 3802 AN XY: 719142

African (AFR) AF: 0.000790 AC: 26 AN: 32894

American (AMR) AF: 0.00110 AC: 49 AN: 44430

Ashkenazi Jewish (ASJ) AF: 0.00459 AC: 119 AN: 25950

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39568

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85884

European-Finnish (FIN) AF: 0.00314 AC: 167 AN: 53268

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5706

European-Non Finnish (NFE) AF: 0.00662 AC: 7255 AN: 1095390

Other (OTH) AF: 0.00380 AC: 227 AN: 59662

GnomAD4 genome AF: 0.00397 AC: 605 AN: 152248 Hom.: 3 Cov.: 32 AF XY: 0.00344 AC XY: 256 AN XY: 74430

African (AFR) AF: 0.000891 AC: 37 AN: 41544

American (AMR) AF: 0.000784 AC: 12 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10598

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

European-Non Finnish (NFE) AF: 0.00763 AC: 519 AN: 68006

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00630 Hom.: 1

Bravo AF: 0.00356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cornelia de Lange syndrome 4 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.76
PhyloP100		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0012
dbscSNV1_RF	Benign	0.24
SpliceAI score (max)		0.010		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: rs200333487; hg19: chr8-117866718;