6-29556175-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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.

• 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
• Publications: 36 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=0.0015520453).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.289 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBD	NM_006398.4	MANE Select	c.203T>C	p.Ile68Thr	missense	Exon 2 of 2	NP_006389.2
	OR2I1	NM_001396058.1	MANE Select	c.*2009A>G		3_prime_UTR	Exon 2 of 2	NP_001382987.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBD	ENST00000377050.5	TSL:1 MANE Select	c.203T>C	p.Ile68Thr	missense	Exon 2 of 2	ENSP00000366249.4
	OR2I1P	ENST00000641137.2	MANE Select	c.*2009A>G		3_prime_UTR	Exon 2 of 2	ENSP00000493715.1
	OR2I1P	ENST00000641730.1		n.3819A>G		non_coding_transcript_exon	Exon 2 of 2

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

GnomAD2 exomes AF: 0.249 AC: 61461 AN: 246476 AF XY: 0.260

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 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

African (AFR) AF: 0.0533 AC: 1783 AN: 33478

American (AMR) AF: 0.163 AC: 7308 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 4146 AN: 26136

East Asian (EAS) AF: 0.180 AC: 7134 AN: 39700

South Asian (SAS) AF: 0.325 AC: 28023 AN: 86250

European-Finnish (FIN) AF: 0.396 AC: 20732 AN: 52314

Middle Eastern (MID) AF: 0.282 AC: 1627 AN: 5768

European-Non Finnish (NFE) AF: 0.257 AC: 285662 AN: 1111938

Other (OTH) AF: 0.244 AC: 14709 AN: 60382

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

African (AFR) AF: 0.0636 AC: 2642 AN: 41532

American (AMR) AF: 0.174 AC: 2651 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 547 AN: 3472

East Asian (EAS) AF: 0.194 AC: 998 AN: 5156

South Asian (SAS) AF: 0.302 AC: 1450 AN: 4808

European-Finnish (FIN) AF: 0.406 AC: 4289 AN: 10558

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.267 AC: 18138 AN: 67962

Other (OTH) AF: 0.207 AC: 437 AN: 2110

Alfa AF: 0.236 Hom.: 13140

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 v4.9

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
PhyloP100		0.64
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
Mutation Taster		=97/3	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: rs2076485; hg19: chr6-29523952; COSMIC: COSV63542234;