chr8-116847643-A-G

Position:

• chr8-116847643-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_006265.3(RAD21):​c.1753T>C​(p.Cys585Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAD21 NM_006265.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 O:1
• Conservation: PhyloP100: 9.31

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]

LOC112268030 (HGNC:):

UTP23 (HGNC:28224): (UTP23 small subunit processome component) Enables mRNA 3'-UTR binding activity and mRNA 5'-UTR binding activity. Predicted to be involved in rRNA processing. Predicted to act upstream of or within endonucleolytic cleavage in 5'-ETS of tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA). Predicted to be part of small-subunit processome. Predicted to be active in nucleolus. Implicated in colorectal adenocarcinoma. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RAD21. . Gene score misZ 2.6421 (greater than the threshold 3.09). Trascript score misZ 3.6451 (greater than threshold 3.09). GenCC has associacion of gene with Cornelia de Lange syndrome, Cornelia de Lange syndrome 4, Mungan syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926
• PP5: Variant 8-116847643-A-G is Pathogenic according to our data. Variant chr8-116847643-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35460.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=1, Pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD21	NM_006265.3	c.1753T>C	p.Cys585Arg	missense_variant	14/14	ENST00000297338.7
LOC112268030	XR_002956724.2	n.761-1245A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD21	ENST00000297338.7	c.1753T>C	p.Cys585Arg	missense_variant	14/14	1	NM_006265.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cornelia de Lange syndrome 4 Pathogenic:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Oct 22, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 08, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 17, 2021	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RAD21 function (PMID: 22633399). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 35460). This missense change has been observed in individual(s) with Cornelia de Lange syndrome (PMID: 22633399, 32193685; external communication). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 585 of the RAD21 protein (p.Cys585Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. -

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2023	Reported in a family with Cornelia de Lange syndrome; however, information about parental testing was not provided (PMID: 32193685); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22633399, 20301283, 24038889, 30716475, 23882154, 32687945, 32193685, 30125677, 25575569, 27882533) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 22, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;.;.;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T;T;T;T
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.7	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.6	D;D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.99	D;.;.;.
Vest4		0.89
MutPred		0.75		Gain of disorder (P = 0.0076);.;.;.;
MVP		0.91
MPC		1.6
ClinPred		0.99	D
GERP RS		6.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.98
gMVP		0.78

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: rs387907213; hg19: chr8-117859882;