NM_133510.4:c.2T>C

Variant names:

• chr14-67823545-T-C
• NM_133510.4:c.2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_133510.4(RAD51B):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000137 in 1,461,328 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RAD51B NM_133510.4 start_lost
• 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 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 39 codons. Genomic position: 67825494. Lost 0.109 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.2T>C	p.Met1?	start_lost	Exon 2 of 11	NP_598194.1	O15315-2
	RAD51B	NM_001321821.2		c.2T>C	p.Met1?	start_lost	Exon 2 of 11	NP_001308750.1	C9JYJ0
	RAD51B	NM_133509.5		c.2T>C	p.Met1?	start_lost	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.2T>C	p.Met1?	start_lost	Exon 2 of 11	ENSP00000418859.1	O15315-2
	RAD51B	ENST00000487861.5	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 2 of 11	ENSP00000419881.1	C9JYJ0
	RAD51B	ENST00000487270.5	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 2 of 11	ENSP00000419471.1	O15315-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461328 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726970

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111716

Other (OTH) AF: 0.00 AC: 0 AN: 60364

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
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.36	T
PhyloP100		4.7
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.97		Gain of catalytic residue at M1 (P = 0.0066)
MVP		0.81
ClinPred		0.99	D
GERP RS		4.3
PromoterAI		0.0093	Neutral
Varity_R		0.66
gMVP		0.57
Mutation Taster		=19/181	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr14-68290262;