chr15-28114618-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_004667.6(HERC2):c.13907A>G(p.Asn4636Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000246 in 1,460,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
HERC2
NM_004667.6 missense
NM_004667.6 missense
Scores
1
4
13
Clinical Significance
Conservation
PhyloP100: 4.21
Genes affected
HERC2 (HGNC:4868): (HECT and RLD domain containing E3 ubiquitin protein ligase 2) This gene belongs to the HERC gene family that encodes a group of unusually large proteins, which contain multiple structural domains. All members have at least 1 copy of an N-terminal region showing homology to the cell cycle regulator RCC1 and a C-terminal HECT (homologous to E6-AP C terminus) domain found in a number of E3 ubiquitin protein ligases. Genetic variations in this gene are associated with skin/hair/eye pigmentation variability. Multiple pseudogenes of this gene are located on chromosomes 15 and 16. [provided by RefSeq, Mar 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, HERC2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.3941998).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HERC2 | NM_004667.6 | c.13907A>G | p.Asn4636Ser | missense_variant | 90/93 | ENST00000261609.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HERC2 | ENST00000261609.13 | c.13907A>G | p.Asn4636Ser | missense_variant | 90/93 | 1 | NM_004667.6 | P1 | |
HERC2 | ENST00000566635.5 | n.1032A>G | non_coding_transcript_exon_variant | 4/7 | 1 | ||||
HERC2 | ENST00000650509.1 | c.*1021A>G | 3_prime_UTR_variant, NMD_transcript_variant | 36/39 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD3 exomes AF: 0.00000799 AC: 2AN: 250400Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135374
GnomAD3 exomes
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GnomAD4 exome AF: 0.0000246 AC: 36AN: 1460990Hom.: 0 Cov.: 34 AF XY: 0.0000234 AC XY: 17AN XY: 726718
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GnomAD4 genome ? Cov.: 31
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31
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 08, 2023 | The c.13907A>G (p.N4636S) alteration is located in exon 90 (coding exon 89) of the HERC2 gene. This alteration results from a A to G substitution at nucleotide position 13907, causing the asparagine (N) at amino acid position 4636 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Benign
T
Polyphen
B
Vest4
MutPred
Loss of catalytic residue at N4636 (P = 0.1417);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at