rs138247094

Positions:

• chr8-116852685-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_006265.3(RAD21):​c.1185G>A​(p.Pro395=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000431 in 1,581,750 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (1 hom.)
• Consequence: RAD21 NM_006265.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.532

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 8-116852685-C-T is Benign according to our data. Variant chr8-116852685-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.532 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000264 (39/147962) while in subpopulation AMR AF= 0.000473 (7/14800). AF 95% confidence interval is 0.000221. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD21	NM_006265.3	c.1185G>A	p.Pro395=	synonymous_variant	10/14	ENST00000297338.7	NP_006256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD21	ENST00000297338.7	c.1185G>A	p.Pro395=	synonymous_variant	10/14	1	NM_006265.3	ENSP00000297338	P1

Frequencies

GnomAD3 genomes AF: 0.000264 AC: 39 AN: 147866 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000474

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000392

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000312

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000323 AC: 75 AN: 232468 Hom.: 0 AF XY: 0.000301 AC XY: 38 AN XY: 126088

Gnomad AFR exome AF: 0.0000655

Gnomad AMR exome AF: 0.000371

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000596

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000540

Gnomad OTH exome AF: 0.000725

GnomAD4 exome AF: 0.000448 AC: 642 AN: 1433788 Hom.: 1 Cov.: 30 AF XY: 0.000450 AC XY: 321 AN XY: 712548

Gnomad4 AFR exome AF: 0.0000312

Gnomad4 AMR exome AF: 0.000519

Gnomad4 ASJ exome AF: 0.0000395

Gnomad4 EAS exome AF: 0.000333

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000519

Gnomad4 OTH exome AF: 0.000592

GnomAD4 genome AF: 0.000264 AC: 39 AN: 147962 Hom.: 0 Cov.: 32 AF XY: 0.000223 AC XY: 16 AN XY: 71842

Gnomad4 AFR AF: 0.000226

Gnomad4 AMR AF: 0.000473

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000393

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000312

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000507 Hom.: 0

Bravo AF: 0.000291

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2017

This alteration is classified as likely 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. -

Cornelia de Lange syndrome 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

RAD21: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	9.8
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs138247094; hg19: chr8-117864924;