8-116852713-TAAAAA-TAAAAAA

Variant names:

• chr8-116852713-T-TA
• rs369816312
• NM_006265.3:c.1162-6dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_006265.3(RAD21):​c.1162-6dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,001,044 control chromosomes in the GnomAD database, including 118 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.026 (115 hom., cov: 31)
  • Exomes 𝑓: 0.20 (3 hom.)
• Consequence: RAD21 NM_006265.3 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.189
• Publications: 3 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 -10 ACMG points.

• BP6: Variant 8-116852713-T-TA is Benign according to our data. Variant chr8-116852713-T-TA is described in ClinVar as Benign. ClinVar VariationId is 1242028.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD21	NM_006265.3	c.1162-6dupT		splice_region_variant, intron_variant	Intron 9 of 13	ENST00000297338.7	NP_006256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD21	ENST00000297338.7	c.1162-6dupT		splice_region_variant, intron_variant	Intron 9 of 13	1	NM_006265.3	ENSP00000297338.2

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 3475 AN: 135176 Hom.: 115 Cov.: 31

Gnomad AFR AF: 0.0805

Gnomad AMI AF: 0.00117

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00247

Gnomad EAS AF: 0.00106

Gnomad SAS AF: 0.00164

Gnomad FIN AF: 0.00543

Gnomad MID AF: 0.0106

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.0224

GnomAD2 exomes AF: 0.0971 AC: 8462 AN: 87152 AF XY: 0.0980

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.0941

Gnomad FIN exome AF: 0.142

Gnomad NFE exome AF: 0.0800

Gnomad OTH exome AF: 0.0944

GnomAD4 exome AF: 0.199 AC: 172139 AN: 865830 Hom.: 3 Cov.: 2 AF XY: 0.196 AC XY: 83491 AN XY: 426994

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.231 AC: 4453 AN: 19252

American (AMR) AF: 0.137 AC: 2379 AN: 17326

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 2588 AN: 14474

East Asian (EAS) AF: 0.208 AC: 4659 AN: 22356

South Asian (SAS) AF: 0.144 AC: 5735 AN: 39858

European-Finnish (FIN) AF: 0.165 AC: 5318 AN: 32188

Middle Eastern (MID) AF: 0.126 AC: 440 AN: 3482

European-Non Finnish (NFE) AF: 0.205 AC: 139333 AN: 681176

Other (OTH) AF: 0.203 AC: 7234 AN: 35718

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0258 AC: 3487 AN: 135214 Hom.: 115 Cov.: 31 AF XY: 0.0259 AC XY: 1691 AN XY: 65196

African (AFR) AF: 0.0807 AC: 2994 AN: 37120

American (AMR) AF: 0.0122 AC: 164 AN: 13484

Ashkenazi Jewish (ASJ) AF: 0.00247 AC: 8 AN: 3238

East Asian (EAS) AF: 0.00106 AC: 5 AN: 4714

South Asian (SAS) AF: 0.00165 AC: 7 AN: 4242

European-Finnish (FIN) AF: 0.00543 AC: 41 AN: 7546

Middle Eastern (MID) AF: 0.0115 AC: 3 AN: 260

European-Non Finnish (NFE) AF: 0.00357 AC: 221 AN: 61872

Other (OTH) AF: 0.0228 AC: 43 AN: 1884

Alfa AF: 0.000791 Hom.: 1

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 24, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19
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: rs369816312; hg19: chr8-117864952; COSMIC: COSV105903080;