chr14-67823622-T-C

Variant names:

• chr14-67823622-T-C
• NM_133510.4:c.79T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_133510.4(RAD51B):​c.79T>C​(p.Cys27Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,458,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. C27C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: RAD51B NM_133510.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.71
• Publications: 0 publications found

Genes affected

RAD51B (HGNC:9822): (RAD51 paralog B) The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are evolutionarily conserved proteins essential for DNA repair by homologous recombination. This protein has been shown to form a stable heterodimer with the family member RAD51C, which further interacts with the other family members, such as RAD51, XRCC2, and XRCC3. Overexpression of this gene was found to cause cell cycle G1 delay and cell apoptosis, which suggested a role of this protein in sensing DNA damage. Rearrangements between this locus and high mobility group AT-hook 2 (HMGA2, GeneID 8091) have been observed in uterine leiomyomata. [provided by RefSeq, Mar 2016]

RAD51B Gene-Disease associations (from GenCC):

• primary ovarian failure

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133510.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51B	NM_133510.4	MANE Select	c.79T>C	p.Cys27Arg	missense	Exon 2 of 11	NP_598194.1	O15315-2
	RAD51B	NM_001321821.2		c.79T>C	p.Cys27Arg	missense	Exon 2 of 11	NP_001308750.1	C9JYJ0
	RAD51B	NM_133509.5		c.79T>C	p.Cys27Arg	missense	Exon 2 of 11	NP_598193.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51B	ENST00000471583.6	TSL:1 MANE Select	c.79T>C	p.Cys27Arg	missense	Exon 2 of 11	ENSP00000418859.1	O15315-2
	RAD51B	ENST00000487861.5	TSL:1	c.79T>C	p.Cys27Arg	missense	Exon 2 of 11	ENSP00000419881.1	C9JYJ0
	RAD51B	ENST00000487270.5	TSL:1	c.79T>C	p.Cys27Arg	missense	Exon 2 of 11	ENSP00000419471.1	O15315-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1458252 Hom.: 0 Cov.: 29 AF XY: 0.0000152 AC XY: 11 AN XY: 725288

African (AFR) AF: 0.00 AC: 0 AN: 33366

American (AMR) AF: 0.00 AC: 0 AN: 44300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 85294

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1110258

Other (OTH) AF: 0.0000166 AC: 1 AN: 60264

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.67		Gain of catalytic residue at L31 (P = 0.0208)
MVP		0.81
MPC		0.94
ClinPred		0.99	D
GERP RS		5.5
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.78
Mutation Taster		=50/50

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

hg19: chr14-68290339;