6-29556175-A-G

Variant names:

• chr6-29556175-A-G
• rs2076485
• NM_006398.4:c.203T>C

Variant summary

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

The NM_006398.4(UBD):​c.203T>C​(p.Ile68Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 1,612,762 control chromosomes in the GnomAD database, including 53,834 homozygotes. In-silico tool predicts 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 0.21 (4056 hom., cov: 32)
  • Exomes 𝑓: 0.25 (49778 hom.)
• Consequence: UBD NM_006398.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.639

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=0.0015520453).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBD	NM_006398.4	c.203T>C	p.Ile68Thr	missense_variant	Exon 2 of 2	ENST00000377050.5	NP_006389.2
OR2I1P	NM_001396058.1	c.*2009A>G		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.203T>C	p.Ile68Thr	missense_variant	Exon 2 of 2	1	NM_006398.4	ENSP00000366249.4
OR2I1P	ENST00000641137.2	c.*2009A>G		3_prime_UTR_variant	Exon 2 of 2		NM_001396058.1	ENSP00000493715.1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31369 AN: 151960 Hom.: 4045 Cov.: 32

Gnomad AFR AF: 0.0636

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.199

GnomAD3 exomes AF: 0.249 AC: 61461 AN: 246476 Hom.: 8622 AF XY: 0.260 AC XY: 34928 AN XY: 134308

Gnomad AFR exome AF: 0.0552

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.153

Gnomad EAS exome AF: 0.183

Gnomad SAS exome AF: 0.332

Gnomad FIN exome AF: 0.402

Gnomad NFE exome AF: 0.271

Gnomad OTH exome AF: 0.257

GnomAD4 exome AF: 0.254 AC: 371124 AN: 1460684 Hom.: 49778 Cov.: 59 AF XY: 0.256 AC XY: 186144 AN XY: 726648

Gnomad4 AFR exome AF: 0.0533

Gnomad4 AMR exome AF: 0.163

Gnomad4 ASJ exome AF: 0.159

Gnomad4 EAS exome AF: 0.180

Gnomad4 SAS exome AF: 0.325

Gnomad4 FIN exome AF: 0.396

Gnomad4 NFE exome AF: 0.257

Gnomad4 OTH exome AF: 0.244

GnomAD4 genome AF: 0.206 AC: 31384 AN: 152078 Hom.: 4056 Cov.: 32 AF XY: 0.213 AC XY: 15797 AN XY: 74314

Gnomad4 AFR AF: 0.0636

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.194

Gnomad4 SAS AF: 0.302

Gnomad4 FIN AF: 0.406

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.207

Alfa AF: 0.245 Hom.: 8817

Bravo AF: 0.179

TwinsUK AF: 0.252 AC: 936

ALSPAC AF: 0.243 AC: 937

ESP6500AA AF: 0.0678 AC: 205

ESP6500EA AF: 0.263 AC: 1423

ExAC AF: 0.251 AC: 29697

Asia WGS AF: 0.332 AC: 1152 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.16	N
MetaRNN	Benign	0.0016	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.086
MPC		0.68
ClinPred		0.044	T
GERP RS		3.0
Varity_R		0.39
gMVP		0.24

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: rs2076485; hg19: chr6-29523952; COSMIC: COSV63542234;