rs2076484

Positions:

• chr6-29556226-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006398.4(UBD):​c.152T>C​(p.Leu51Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0569 in 1,612,944 control chromosomes in the GnomAD database, including 10,453 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (4399 hom., cov: 32)
  • Exomes 𝑓: 0.046 (6054 hom.)
• Consequence: UBD NM_006398.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.385

Genes affected

UBD (HGNC:18795): (ubiquitin D) This gene encodes a protein which contains two ubiquitin-like domains and appears to have similar function to ubiquitin. Through covalent attachment, the encoded protein targets other proteins for 26S proteasome degradation. This protein has been implicated to function in many cellular processes, including caspase-dependent apoptosis, formation of aggresomes, mitotic regulation, and dendritic cell maturation. Upregulation of this gene may promote inflammation in chronic kidney disease and has been observed in many cancer types. [provided by RefSeq, Aug 2017]

OR2I1P (HGNC:8258): (olfactory receptor family 2 subfamily I member 1 pseudogene) Olfactory receptors interact with odorant molecules in the nose, to initiate a neuronal response that triggers the perception of a smell. The olfactory receptor proteins are members of a large family of G-protein-coupled receptors (GPCR) arising from single coding-exon genes. Olfactory receptors share a 7-transmembrane domain structure with many neurotransmitter and hormone receptors and are responsible for the recognition and G protein-mediated transduction of odorant signals. The olfactory receptor gene family is the largest in the genome. The nomenclature assigned to the olfactory receptor genes and proteins for this organism is independent of other organisms. [provided by RefSeq, Jul 2008]

GABBR1 (HGNC:4070): (gamma-aminobutyric acid type B receptor subunit 1) This gene encodes a receptor for gamma-aminobutyric acid (GABA), which is the main inhibitory neurotransmitter in the mammalian central nervous system. This receptor functions as a heterodimer with GABA(B) receptor 2. Defects in this gene may underlie brain disorders such as schizophrenia and epilepsy. Alternative splicing generates multiple transcript variants, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038864017).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBD	NM_006398.4	c.152T>C	p.Leu51Ser	missense_variant	2/2	ENST00000377050.5	NP_006389.2
OR2I1P	NM_001396058.1	c.*2060A>G		3_prime_UTR_variant	2/2	ENST00000641137.2	NP_001382987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBD	ENST00000377050.5	c.152T>C	p.Leu51Ser	missense_variant	2/2	1	NM_006398.4	ENSP00000366249.4
OR2I1P	ENST00000641137.2	c.*2060A>G		3_prime_UTR_variant	2/2		NM_001396058.1	ENSP00000493715.1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23922 AN: 152078 Hom.: 4367 Cov.: 32

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0917

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.00960

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0250

Gnomad OTH AF: 0.160

GnomAD3 exomes AF: 0.0819 AC: 20203 AN: 246596 Hom.: 2271 AF XY: 0.0774 AC XY: 10407 AN XY: 134380

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.0761

Gnomad ASJ exome AF: 0.0998

Gnomad EAS exome AF: 0.161

Gnomad SAS exome AF: 0.115

Gnomad FIN exome AF: 0.00851

Gnomad NFE exome AF: 0.0248

Gnomad OTH exome AF: 0.0665

GnomAD4 exome AF: 0.0464 AC: 67846 AN: 1460748 Hom.: 6054 Cov.: 35 AF XY: 0.0479 AC XY: 34842 AN XY: 726688

Gnomad4 AFR exome AF: 0.457

Gnomad4 AMR exome AF: 0.0796

Gnomad4 ASJ exome AF: 0.0949

Gnomad4 EAS exome AF: 0.180

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.00856

Gnomad4 NFE exome AF: 0.0205

Gnomad4 OTH exome AF: 0.0745

GnomAD4 genome AF: 0.158 AC: 23998 AN: 152196 Hom.: 4399 Cov.: 32 AF XY: 0.156 AC XY: 11614 AN XY: 74426

Gnomad4 AFR AF: 0.442

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.0917

Gnomad4 EAS AF: 0.150

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.00960

Gnomad4 NFE AF: 0.0250

Gnomad4 OTH AF: 0.158

Alfa AF: 0.0585 Hom.: 1891

Bravo AF: 0.181

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.439 AC: 1326

ESP6500EA AF: 0.0282 AC: 153

ExAC AF: 0.0879 AC: 10379

Asia WGS AF: 0.137 AC: 476 AN: 3478

EpiCase AF: 0.0318

EpiControl AF: 0.0335

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	3.6
DANN	Benign	0.82
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.010	N
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.15
Sift	Benign	0.13	T
Sift4G	Benign	0.22	T
Polyphen		0.058	B
Vest4		0.046
MPC		0.35
ClinPred		0.0073	T
GERP RS		-8.2
Varity_R		0.14
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2076484; hg19: chr6-29524003;