6-29556082-G-C

Variant names:

• chr6-29556082-G-C
• rs2076487
• NM_006398.4:c.296C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006398.4(UBD):​c.296C>G​(p.Ala99Gly) 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 1,612,922 control chromosomes in the GnomAD database, including 10,448 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 (4394 hom., cov: 32)
  • Exomes 𝑓: 0.046 (6054 hom.)
• Consequence: UBD NM_006398.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06
• 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=0.0014770031).
• 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 rank	MANE	Protein	UniProt
UBD	NM_006398.4	c.296C>G	p.Ala99Gly	missense_variant	Exon 2 of 2	ENST00000377050.5	NP_006389.2
OR2I1	NM_001396058.1	c.*1916G>C		3_prime_UTR_variant	Exon 2 of 2	ENST00000641137.2	NP_001382987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBD	ENST00000377050.5	c.296C>G	p.Ala99Gly	missense_variant	Exon 2 of 2	1	NM_006398.4	ENSP00000366249.4
OR2I1P	ENST00000641137.2	c.*1916G>C		3_prime_UTR_variant	Exon 2 of 2		NM_001396058.1	ENSP00000493715.1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23913 AN: 152002 Hom.: 4362 Cov.: 32

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0911

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.00962

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0250

Gnomad OTH AF: 0.160

GnomAD2 exomes AF: 0.0819 AC: 20217 AN: 246842 AF XY: 0.0774

Gnomad AFR exome AF: 0.451

Gnomad AMR exome AF: 0.0761

Gnomad ASJ exome AF: 0.0997

Gnomad EAS exome AF: 0.161

Gnomad FIN exome AF: 0.00851

Gnomad NFE exome AF: 0.0248

Gnomad OTH exome AF: 0.0664

GnomAD4 exome AF: 0.0464 AC: 67842 AN: 1460802 Hom.: 6054 Cov.: 53 AF XY: 0.0479 AC XY: 34842 AN XY: 726714

African (AFR) AF: 0.457 AC: 15307 AN: 33478

American (AMR) AF: 0.0796 AC: 3562 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0949 AC: 2480 AN: 26134

East Asian (EAS) AF: 0.180 AC: 7161 AN: 39700

South Asian (SAS) AF: 0.127 AC: 10982 AN: 86256

European-Finnish (FIN) AF: 0.00855 AC: 448 AN: 52370

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

European-Non Finnish (NFE) AF: 0.0205 AC: 22778 AN: 1111990

Other (OTH) AF: 0.0744 AC: 4494 AN: 60382

GnomAD4 genome AF: 0.158 AC: 23989 AN: 152120 Hom.: 4394 Cov.: 32 AF XY: 0.156 AC XY: 11606 AN XY: 74386

African (AFR) AF: 0.443 AC: 18341 AN: 41446

American (AMR) AF: 0.109 AC: 1672 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0911 AC: 316 AN: 3468

East Asian (EAS) AF: 0.150 AC: 776 AN: 5174

South Asian (SAS) AF: 0.148 AC: 713 AN: 4820

European-Finnish (FIN) AF: 0.00962 AC: 102 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0250 AC: 1700 AN: 68004

Other (OTH) AF: 0.157 AC: 332 AN: 2110

Alfa AF: 0.0423 Hom.: 374

Bravo AF: 0.181

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.439 AC: 1326

ESP6500EA AF: 0.0282 AC: 153

ExAC AF: 0.0872 AC: 10389

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	0.045
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.0
DANN	Benign	0.68
DEOGEN2	Benign	0.060	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00040	N
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-3.1	N
PhyloP100		2.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	5.0	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.018
MPC		0.13
ClinPred		0.0051	T
GERP RS		5.2
Varity_R		0.040
gMVP		0.10
Mutation Taster		=99/1	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: rs2076487; hg19: chr6-29523859; COSMIC: COSV63543715;