chr19-45001656-C-A

Variant names:

• chr19-45001656-C-A
• rs747010962
• NM_006509.4:c.77C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006509.4(RELB):​c.77C>A​(p.Pro26Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,370,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P26L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: RELB NM_006509.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.751

Genes affected

RELB (HGNC:9956): (RELB proto-oncogene, NF-kB subunit) Enables RNA polymerase II cis-regulatory region sequence-specific DNA binding activity and protein kinase binding activity. Involved in lymphocyte differentiation and negative regulation of interferon-beta production. Located in cytosol and nucleoplasm. Part of chromatin; nucleus; and transcription repressor complex. Colocalizes with centrosome. Implicated in breast cancer and immunodeficiency 53. Biomarker of breast cancer and transitional cell carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056124747).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELB	NM_006509.4	c.77C>A	p.Pro26Gln	missense_variant	Exon 1 of 12	ENST00000221452.13	NP_006500.2
RELB	NM_001411087.1	c.77C>A	p.Pro26Gln	missense_variant	Exon 1 of 11		NP_001398016.1
RELB	XM_005259128.3	c.77C>A	p.Pro26Gln	missense_variant	Exon 1 of 11		XP_005259185.1
RELB	XM_047439189.1	c.-388C>A		5_prime_UTR_variant	Exon 1 of 13		XP_047295145.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELB	ENST00000221452.13	c.77C>A	p.Pro26Gln	missense_variant	Exon 1 of 12	1	NM_006509.4	ENSP00000221452.7
RELB	ENST00000505236.2	c.77C>A	p.Pro26Gln	missense_variant	Exon 1 of 11	5		ENSP00000423287.1
RELB	ENST00000509480.5	n.77C>A		non_coding_transcript_exon_variant	Exon 1 of 5	3		ENSP00000427348.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1370470 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 675802

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.32e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.55	.;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.056	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.090	N;.;N
REVEL	Benign	0.0080
Sift	Benign	0.11	T;.;T
Sift4G	Benign	0.097	T;T;T
Polyphen		0.016	.;.;B
Vest4		0.14
MutPred		0.20		Loss of catalytic residue at P26 (P = 0.0059);Loss of catalytic residue at P26 (P = 0.0059);Loss of catalytic residue at P26 (P = 0.0059);
MVP		0.28
MPC		0.54
ClinPred		0.16	T
GERP RS		0.68
Varity_R		0.042
gMVP		0.12

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

Publications

LitVar

Other links and lift over

dbSNP: rs747010962; hg19: chr19-45504914;