Variant 17-5132431-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001304284.2(USP6):c.191C>T(p.Ala64Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000614 in 1,612,038 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000061 ( 1 hom. )

Consequence

USP6
NM_001304284.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.47

Variant links:

Genes affected

USP6 (HGNC:12629): (ubiquitin specific peptidase 6) Enables thiol-dependent deubiquitinase. Involved in protein deubiquitination and regulation of vesicle-mediated transport. Located in plasma membrane and recycling endosome. [provided by Alliance of Genome Resources, Apr 2022]

USP6 links:

USP6 (HGNC:):

USP6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008441061).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP6	NM_001304284.2 linkuse as main transcript	c.191C>T	p.Ala64Val	missense_variant	12/38	ENST00000574788.6	NP_001291213.1	P35125-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP6	ENST00000574788.6 linkuse as main transcript	c.191C>T	p.Ala64Val	missense_variant	12/38	1	NM_001304284.2	ENSP00000460380.1		P35125-1

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000231

AC:

AN:

250792

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135674

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000610

AC:

AN:

1459830

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

726230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00105

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00200

Hom.:

Bravo

AF:

0.000181

ExAC

AF:

0.000189

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2023

The c.191C>T (p.A64V) alteration is located in exon 4 (coding exon 3) of the USP6 gene. This alteration results from a C to T substitution at nucleotide position 191, causing the alanine (A) at amino acid position 64 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.0034

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.60

.;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.0084

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.96

L;L

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.48

.;N

REVEL

Benign

0.17

Sift

Benign

0.55

.;T

Sift4G

Benign

0.48

T;T

Polyphen

0.0

B;B

Vest4

0.088

MutPred

0.29

Gain of methylation at K65 (P = 0.0389);Gain of methylation at K65 (P = 0.0389);

MVP

0.20

MPC

0.23

ClinPred

0.0086

Varity_R

0.049

gMVP

0.32

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over