Variant 17-5135279-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001304284.2(USP6):c.540C>A(p.Asn180Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,684 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

USP6
NM_001304284.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.30

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USP6	NM_001304284.2 linkuse as main transcript	c.540C>A	p.Asn180Lys	missense_variant	16/38	ENST00000574788.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP6	ENST00000574788.6 linkuse as main transcript	c.540C>A	p.Asn180Lys	missense_variant	16/38	1	NM_001304284.2	P1	P35125-1
USP6	ENST00000250066.6 linkuse as main transcript	c.540C>A	p.Asn180Lys	missense_variant	8/30	1		P1	P35125-1
USP6	ENST00000572949.5 linkuse as main transcript	c.540C>A	p.Asn180Lys	missense_variant, NMD_transcript_variant	8/29	2			P35125-3
USP6	ENST00000575709.5 linkuse as main transcript	c.540C>A	p.Asn180Lys	missense_variant, NMD_transcript_variant	8/31	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460506

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726532

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

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

Sep 14, 2023

The c.540C>A (p.N180K) alteration is located in exon 8 (coding exon 7) of the USP6 gene. This alteration results from a C to A substitution at nucleotide position 540, causing the asparagine (N) at amino acid position 180 to be replaced by a lysine (K). 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

Pathogenic

0.77

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.083

T;T

Eigen

Benign

-0.057

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.85

.;T

M_CAP

Benign

0.010

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Pathogenic

3.0

M;M

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.1

.;N

REVEL

Benign

0.15

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.97

D;D

Vest4

0.32

MutPred

0.70

Gain of methylation at N180 (P = 0.0205);Gain of methylation at N180 (P = 0.0205);

MVP

0.42

MPC

0.71

ClinPred

0.98

GERP RS

0.86

Varity_R

0.24

gMVP

0.50

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