rs1050838

Positions:

• chr8-116851978-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006265.3(RAD21):​c.1440T>C​(p.Ala480Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 1,609,546 control chromosomes in the GnomAD database, including 23,475 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1772 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21703 hom.)
• Consequence: RAD21 NM_006265.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.942

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-116851978-A-G is Benign according to our data. Variant chr8-116851978-A-G is described in ClinVar as [Benign]. Clinvar id is 159805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-116851978-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.942 with no splicing effect.
• 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/exons	MANE	Protein	UniProt
RAD21	NM_006265.3	c.1440T>C	p.Ala480Ala	synonymous_variant	11/14	ENST00000297338.7	NP_006256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD21	ENST00000297338.7	c.1440T>C	p.Ala480Ala	synonymous_variant	11/14	1	NM_006265.3	ENSP00000297338.2

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20675 AN: 152062 Hom.: 1767 Cov.: 32

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.135

GnomAD3 exomes AF: 0.178 AC: 44578 AN: 250998 Hom.: 4325 AF XY: 0.179 AC XY: 24225 AN XY: 135636

Gnomad AFR exome AF: 0.0290

Gnomad AMR exome AF: 0.252

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.181

Gnomad SAS exome AF: 0.201

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.168

Gnomad OTH exome AF: 0.179

GnomAD4 exome AF: 0.169 AC: 246021 AN: 1457366 Hom.: 21703 Cov.: 31 AF XY: 0.170 AC XY: 123575 AN XY: 724814

Gnomad4 AFR exome AF: 0.0276

Gnomad4 AMR exome AF: 0.249

Gnomad4 ASJ exome AF: 0.217

Gnomad4 EAS exome AF: 0.168

Gnomad4 SAS exome AF: 0.206

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.136 AC: 20697 AN: 152180 Hom.: 1772 Cov.: 32 AF XY: 0.139 AC XY: 10325 AN XY: 74400

Gnomad4 AFR AF: 0.0315

Gnomad4 AMR AF: 0.211

Gnomad4 ASJ AF: 0.225

Gnomad4 EAS AF: 0.174

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.170

Gnomad4 NFE AF: 0.166

Gnomad4 OTH AF: 0.136

Alfa AF: 0.163 Hom.: 4530

Bravo AF: 0.134

Asia WGS AF: 0.183 AC: 635 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2017	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. -

Cornelia de Lange syndrome 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Mungan syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.8
DANN	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs1050838; hg19: chr8-117864217; COSMIC: COSV52055885; COSMIC: COSV52055885;