rs138247094

Variant names:

• chr8-116852685-C-T
• rs138247094
• NM_006265.3:c.1185G>A

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.Pro395Pro) 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 rank	MANE	Protein	UniProt
RAD21	NM_006265.3	c.1185G>A	p.Pro395Pro	synonymous_variant	Exon 10 of 14	ENST00000297338.7	NP_006256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD21	ENST00000297338.7	c.1185G>A	p.Pro395Pro	synonymous_variant	Exon 10 of 14	1	NM_006265.3	ENSP00000297338.2

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

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Dec 18, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RAD21: BP4, BP7 -

Cornelia de Lange syndrome 4 Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;