rs2412546

Variant names:

• chr15-40714325-G-A
• rs2412546
• NM_002875.5:c.436-4480G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002875.5(RAD51):​c.436-4480G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 152,044 control chromosomes in the GnomAD database, including 19,615 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (19615 hom., cov: 32)
• Consequence: RAD51 NM_002875.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.663
• Publications: 14 publications found

Genes affected

RAD51 (HGNC:9817): (RAD51 recombinase) The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51, and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with the ssDNA-binding protein RPA and RAD52, and it is thought to play roles in homologous pairing and strand transfer of DNA. This protein is also found to interact with BRCA1 and BRCA2, which may be important for the cellular response to DNA damage. BRCA2 is shown to regulate both the intracellular localization and DNA-binding ability of this protein. Loss of these controls following BRCA2 inactivation may be a key event leading to genomic instability and tumorigenesis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2009]

RAD51 Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group R

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mirror movements 2

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• familial congenital mirror movements

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.753 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51	NM_002875.5	c.436-4480G>A		intron_variant	Intron 5 of 9	ENST00000267868.8	NP_002866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51	ENST00000267868.8	c.436-4480G>A		intron_variant	Intron 5 of 9	1	NM_002875.5	ENSP00000267868.3
RAD51	ENST00000532743.6	c.436-4480G>A		intron_variant	Intron 5 of 9	2		ENSP00000433924.2
RAD51	ENST00000557850.5	c.226-4561G>A		intron_variant	Intron 3 of 7	2		ENSP00000454176.1

Frequencies

GnomAD3 genomes AF: 0.497 AC: 75439 AN: 151926 Hom.: 19598 Cov.: 32

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.601

Gnomad ASJ AF: 0.566

Gnomad EAS AF: 0.772

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.496

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.496 AC: 75481 AN: 152044 Hom.: 19615 Cov.: 32 AF XY: 0.507 AC XY: 37697 AN XY: 74314

African (AFR) AF: 0.364 AC: 15108 AN: 41488

American (AMR) AF: 0.602 AC: 9176 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 1962 AN: 3466

East Asian (EAS) AF: 0.773 AC: 4008 AN: 5188

South Asian (SAS) AF: 0.650 AC: 3127 AN: 4812

European-Finnish (FIN) AF: 0.600 AC: 6343 AN: 10564

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.502 AC: 34140 AN: 67964

Other (OTH) AF: 0.500 AC: 1054 AN: 2108

Alfa AF: 0.506 Hom.: 25992

Bravo AF: 0.493

Asia WGS AF: 0.709 AC: 2465 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.1
DANN	Benign	0.74
PhyloP100		0.66
Mutation Taster		=99/1	polymorphism (auto)

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

dbSNP: rs2412546; hg19: chr15-41006523;