rs3816342

Variant names:

• chr8-116858136-A-G
• rs3816342
• NM_006265.3:c.481+216T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006265.3(RAD21):​c.481+216T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 152,236 control chromosomes in the GnomAD database, including 1,745 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (1745 hom., cov: 32)
• Consequence: RAD21 NM_006265.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.502
• Publications: 8 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Mungan syndrome

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-116858136-A-G is Benign according to our data. Variant chr8-116858136-A-G is described in ClinVar as Benign. ClinVar VariationId is 668613.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD21	NM_006265.3	c.481+216T>C		intron_variant	Intron 5 of 13	ENST00000297338.7	NP_006256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD21	ENST00000297338.7	c.481+216T>C		intron_variant	Intron 5 of 13	1	NM_006265.3	ENSP00000297338.2

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20579 AN: 152118 Hom.: 1742 Cov.: 32

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.134

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

GnomAD4 genome AF: 0.135 AC: 20589 AN: 152236 Hom.: 1745 Cov.: 32 AF XY: 0.138 AC XY: 10273 AN XY: 74418

African (AFR) AF: 0.0308 AC: 1282 AN: 41570

American (AMR) AF: 0.211 AC: 3219 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 778 AN: 3472

East Asian (EAS) AF: 0.174 AC: 902 AN: 5186

South Asian (SAS) AF: 0.198 AC: 957 AN: 4828

European-Finnish (FIN) AF: 0.169 AC: 1785 AN: 10578

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.165 AC: 11240 AN: 68000

Other (OTH) AF: 0.135 AC: 286 AN: 2114

Alfa AF: 0.143 Hom.: 261

Bravo AF: 0.133

Asia WGS AF: 0.178 AC: 618 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.7
DANN	Benign	0.44
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs3816342; hg19: chr8-117870375;