NM_001291746.2:c.1082C>G

Variant names:

• chr2-60921853-C-G
• rs34661029
• NM_001291746.2:c.1082C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001291746.2(REL):​c.1082C>G​(p.Pro361Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,614,094 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P361T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0056 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (5 hom.)
• Consequence: REL NM_001291746.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.02
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003190726).
• BP6: Variant 2-60921853-C-G is Benign according to our data. Variant chr2-60921853-C-G is described in ClinVar as Benign. ClinVar VariationId is 790504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00564 (859/152228) while in subpopulation AFR AF = 0.0197 (820/41534). AF 95% confidence interval is 0.0186. There are 7 homozygotes in GnomAd4. There are 388 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.1082C>G	p.Pro361Arg	missense	Exon 10 of 10	NP_001278675.1
	REL	NM_002908.4		c.1178C>G	p.Pro393Arg	missense	Exon 11 of 11	NP_002899.1
	REL	NM_001438025.1		c.1013C>G	p.Pro338Arg	missense	Exon 9 of 9	NP_001424954.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REL	ENST00000394479.4	TSL:1 MANE Select	c.1082C>G	p.Pro361Arg	missense	Exon 10 of 10	ENSP00000377989.4
	REL	ENST00000295025.12	TSL:1	c.1178C>G	p.Pro393Arg	missense	Exon 11 of 11	ENSP00000295025.7
	REL	ENST00000699191.1		c.1013C>G	p.Pro338Arg	missense	Exon 9 of 9	ENSP00000514191.1

Frequencies

GnomAD3 genomes AF: 0.00561 AC: 854 AN: 152110 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00147 AC: 369 AN: 251294 AF XY: 0.00105

Gnomad AFR exome AF: 0.0204

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000539 AC: 788 AN: 1461866 Hom.: 5 Cov.: 32 AF XY: 0.000477 AC XY: 347 AN XY: 727234

African (AFR) AF: 0.0188 AC: 628 AN: 33480

American (AMR) AF: 0.00105 AC: 47 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111998

Other (OTH) AF: 0.00113 AC: 68 AN: 60394

GnomAD4 genome AF: 0.00564 AC: 859 AN: 152228 Hom.: 7 Cov.: 32 AF XY: 0.00521 AC XY: 388 AN XY: 74434

African (AFR) AF: 0.0197 AC: 820 AN: 41534

American (AMR) AF: 0.00190 AC: 29 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.000898 Hom.: 0

Bravo AF: 0.00648

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00180 AC: 219

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.0
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.034
Sift	Benign	0.11	T
Sift4G	Benign	0.37	T
Polyphen		0.18	B
Vest4		0.085
MVP		0.12
MPC		0.027
ClinPred		0.0066	T
GERP RS		3.6
Varity_R		0.049
gMVP		0.24
Mutation Taster		=96/4	polymorphism

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: rs34661029; hg19: chr2-61148988; COSMIC: COSV54363101;