rs2076484

Variant names:

• chr6-29556226-A-G
• rs2076484
• NM_006398.4:c.152T>C
• UBD p.Leu51Ser

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 18 publications found

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]

OR2I1 (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]

GABBR1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with language delay and variable cognitive abnormalities

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006398.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBD	NM_006398.4	MANE Select	c.152T>C	p.Leu51Ser	missense	Exon 2 of 2	NP_006389.2	O15205
	OR2I1	NM_001396058.1	MANE Select	c.*2060A>G		3_prime_UTR	Exon 2 of 2	NP_001382987.1	Q8NGU4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBD	ENST00000377050.5	TSL:1 MANE Select	c.152T>C	p.Leu51Ser	missense	Exon 2 of 2	ENSP00000366249.4	O15205
	OR2I1	ENST00000641137.2	MANE Select	c.*2060A>G		3_prime_UTR	Exon 2 of 2	ENSP00000493715.1	Q8NGU4
	UBD	ENST00000866140.1		c.296T>C	p.Leu99Ser	missense	Exon 3 of 3	ENSP00000536199.1

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

GnomAD2 exomes AF: 0.0819 AC: 20203 AN: 246596 AF XY: 0.0774

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 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

African (AFR) AF: 0.457 AC: 15308 AN: 33480

American (AMR) AF: 0.0796 AC: 3562 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0949 AC: 2480 AN: 26136

East Asian (EAS) AF: 0.180 AC: 7161 AN: 39698

South Asian (SAS) AF: 0.127 AC: 10983 AN: 86258

European-Finnish (FIN) AF: 0.00856 AC: 448 AN: 52316

Middle Eastern (MID) AF: 0.109 AC: 630 AN: 5768

European-Non Finnish (NFE) AF: 0.0205 AC: 22777 AN: 1111986

Other (OTH) AF: 0.0745 AC: 4497 AN: 60384

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

African (AFR) AF: 0.442 AC: 18342 AN: 41456

American (AMR) AF: 0.109 AC: 1675 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0917 AC: 318 AN: 3468

East Asian (EAS) AF: 0.150 AC: 775 AN: 5178

South Asian (SAS) AF: 0.148 AC: 715 AN: 4822

European-Finnish (FIN) AF: 0.00960 AC: 102 AN: 10620

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0250 AC: 1701 AN: 68026

Other (OTH) AF: 0.158 AC: 333 AN: 2114

Alfa AF: 0.0728 Hom.: 6328

Bravo AF: 0.181

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 v4.9

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
PhyloP100		-0.39
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.15
Sift	Benign	0.13	T
Sift4G	Benign	0.22	T
Varity_R		0.14
gMVP		0.50
Mutation Taster		=99/1	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2076484;

hg19: chr6-29524003;