2-60899529-A-G

Variant names:

• chr2-60899529-A-G
• rs10193964
• NM_001291746.2:c.303-1463A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001291746.2(REL):​c.303-1463A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 152,328 control chromosomes in the GnomAD database, including 3,427 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 0.20 (3420 hom., cov: 32)
  • Exomes 𝑓: 0.31 (7 hom.)
• Consequence: REL NM_001291746.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71
• Publications: 13 publications found

Genes affected

REL (HGNC:9954): (REL proto-oncogene, NF-kB subunit) This gene encodes a protein that belongs to the Rel homology domain/immunoglobulin-like fold, plexin, transcription factor (RHD/IPT) family. Members of this family regulate genes involved in apoptosis, inflammation, the immune response, and oncogenic processes. This proto-oncogene plays a role in the survival and proliferation of B lymphocytes. Mutation or amplification of this gene is associated with B-cell lymphomas, including Hodgkin's lymphoma. Single nucleotide polymorphisms in this gene are associated with susceptibility to ulcerative colitis and rheumatoid arthritis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2014]

REL Gene-Disease associations (from GenCC):

• immunodeficiency 92

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291746.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REL	NM_001291746.2	MANE Select	c.303-1463A>G		intron	N/A	NP_001278675.1
	REL	NM_002908.4		c.303-1463A>G		intron	N/A	NP_002899.1
	REL	NM_001438025.1		c.303-1463A>G		intron	N/A	NP_001424954.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REL	ENST00000394479.4	TSL:1 MANE Select	c.303-1463A>G		intron	N/A	ENSP00000377989.4
	REL	ENST00000295025.12	TSL:1	c.303-1463A>G		intron	N/A	ENSP00000295025.7
	REL	ENST00000642725.1		n.709A>G		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30939 AN: 152060 Hom.: 3421 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.00885

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.241

GnomAD4 exome AF: 0.313 AC: 47 AN: 150 Hom.: 7 Cov.: 0 AF XY: 0.345 AC XY: 29 AN XY: 84

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.318 AC: 42 AN: 132

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.286 AC: 4 AN: 14

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.203 AC: 30945 AN: 152178 Hom.: 3420 Cov.: 32 AF XY: 0.202 AC XY: 15007 AN XY: 74390

African (AFR) AF: 0.150 AC: 6239 AN: 41532

American (AMR) AF: 0.174 AC: 2664 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1237 AN: 3470

East Asian (EAS) AF: 0.00887 AC: 46 AN: 5188

South Asian (SAS) AF: 0.129 AC: 621 AN: 4832

European-Finnish (FIN) AF: 0.278 AC: 2936 AN: 10568

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16341 AN: 67986

Other (OTH) AF: 0.240 AC: 507 AN: 2114

Alfa AF: 0.226 Hom.: 6277

Bravo AF: 0.192

Asia WGS AF: 0.0740 AC: 256 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.95
PhyloP100		1.7
Mutation Taster		=100/0	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: rs10193964; hg19: chr2-61126664; COSMIC: COSV54362535;