10-11462884-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014688.5(USP6NL):ā€‹c.2044G>Cā€‹(p.Glu682Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.000016 ( 0 hom. )

Consequence

USP6NL
NM_014688.5 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.13
Variant links:
Genes affected
USP6NL (HGNC:16858): (USP6 N-terminal like) Enables GTPase activator activity and small GTPase binding activity. Involved in several processes, including plasma membrane to endosome transport; positive regulation of GTPase activity; and retrograde transport, plasma membrane to Golgi. Located in cytoplasmic vesicle and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.10528371).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
USP6NLNM_014688.5 linkuse as main transcriptc.2044G>C p.Glu682Gln missense_variant 15/15 ENST00000609104.6 NP_055503.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
USP6NLENST00000609104.6 linkuse as main transcriptc.2044G>C p.Glu682Gln missense_variant 15/151 NM_014688.5 ENSP00000476462 P1Q92738-1
USP6NLENST00000379237.6 linkuse as main transcriptc.2113G>C p.Glu705Gln missense_variant 14/145 ENSP00000368539
USP6NLENST00000277575.5 linkuse as main transcriptc.2095G>C p.Glu699Gln missense_variant 14/145 ENSP00000277575 Q92738-2

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152134
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000386
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:
0.0000282
AC:
7
AN:
248354
Hom.:
0
AF XY:
0.0000445
AC XY:
6
AN XY:
134818
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000167
Gnomad SAS exome
AF:
0.0000982
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000157
AC:
23
AN:
1461460
Hom.:
0
Cov.:
31
AF XY:
0.0000248
AC XY:
18
AN XY:
726996
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.000151
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152134
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74290
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

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 submitterclinical testingAmbry GeneticsJan 30, 2024The c.2095G>C (p.E699Q) alteration is located in exon 14 (coding exon 14) of the USP6NL gene. This alteration results from a G to C substitution at nucleotide position 2095, causing the glutamic acid (E) at amino acid position 699 to be replaced by a glutamine (Q). 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
0.11
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
14
DANN
Uncertain
0.99
DEOGEN2
Benign
0.13
T;.;.
Eigen
Benign
-0.055
Eigen_PC
Benign
-0.13
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Benign
0.0081
T
MetaRNN
Benign
0.11
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
2.0
M;.;.
MutationTaster
Benign
0.86
N;N;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.76
.;N;.
REVEL
Benign
0.089
Sift
Uncertain
0.015
.;D;.
Sift4G
Benign
0.36
T;T;T
Polyphen
0.92
P;P;.
Vest4
0.095
MutPred
0.083
Loss of ubiquitination at K683 (P = 0.0487);.;.;
MVP
0.71
MPC
0.38
ClinPred
0.077
T
GERP RS
4.3
Varity_R
0.072
gMVP
0.38

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

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

Other links and lift over

dbSNP: rs765638465; hg19: chr10-11504883; API