6-75647747-C-T

Variant summary

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

The NM_015571.4(SENP6):​c.496C>T​(p.His166Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

SENP6
NM_015571.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.47
Variant links:
Genes affected
SENP6 (HGNC:20944): (SUMO specific peptidase 6) Ubiquitin-like molecules (UBLs), such as SUMO1 (UBL1; MIM 601912), are structurally related to ubiquitin (MIM 191339) and can be ligated to target proteins in a similar manner as ubiquitin. However, covalent attachment of UBLs does not result in degradation of the modified proteins. SUMO1 modification is implicated in the targeting of RANGAP1 (MIM 602362) to the nuclear pore complex, as well as in stabilization of I-kappa-B-alpha (NFKBIA; MIM 164008) from degradation by the 26S proteasome. Like ubiquitin, UBLs are synthesized as precursor proteins, with 1 or more amino acids following the C-terminal glycine-glycine residues of the mature UBL protein. Thus, the tail sequences of the UBL precursors need to be removed by UBL-specific proteases, such as SENP6, prior to their conjugation to target proteins (Kim et al., 2000 [PubMed 10799485]). SENPs also display isopeptidase activity for deconjugation of SUMO-conjugated substrates (Lima and Reverter, 2008 [PubMed 18799455]).[supplied by OMIM, Jun 2009]

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=0.08231774).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SENP6NM_015571.4 linkc.496C>T p.His166Tyr missense_variant Exon 7 of 24 ENST00000447266.7 NP_056386.2 Q9GZR1-1B3KMM0
SENP6NM_001100409.3 linkc.475C>T p.His159Tyr missense_variant Exon 6 of 23 NP_001093879.1 Q9GZR1-2B3KMM0
SENP6NM_001304792.2 linkc.475C>T p.His159Tyr missense_variant Exon 6 of 15 NP_001291721.1 Q9GZR1F8W6D9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SENP6ENST00000447266.7 linkc.496C>T p.His166Tyr missense_variant Exon 7 of 24 1 NM_015571.4 ENSP00000402527.2 Q9GZR1-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 28, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.496C>T (p.H166Y) alteration is located in exon 7 (coding exon 7) of the SENP6 gene. This alteration results from a C to T substitution at nucleotide position 496, causing the histidine (H) at amino acid position 166 to be replaced by a tyrosine (Y). 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
0.085
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
23
DANN
Benign
0.97
DEOGEN2
Benign
0.0058
.;.;T;.;T
Eigen
Benign
-0.21
Eigen_PC
Benign
-0.036
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.84
T;T;T;T;T
M_CAP
Benign
0.0063
T
MetaRNN
Benign
0.082
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.3
.;.;L;.;.
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.3
N;N;N;D;N
REVEL
Benign
0.033
Sift
Benign
0.19
T;T;T;T;T
Sift4G
Benign
0.20
T;T;T;T;T
Polyphen
0.0070
B;B;B;.;.
Vest4
0.31
MutPred
0.18
.;.;Gain of phosphorylation at H166 (P = 0.0325);.;.;
MVP
0.082
MPC
0.55
ClinPred
0.90
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.059
gMVP
0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-76357463; API