rs1057519727
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
The NM_004667.6(HERC2):āc.2264T>Cā(p.Leu755Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
HERC2
NM_004667.6 missense
NM_004667.6 missense
Scores
7
6
5
Clinical Significance
Conservation
PhyloP100: 9.24
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 Likely_pathogenic. Variant got 8 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, HERC2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.975
PP5
?
Variant 15-28260829-A-G is Pathogenic according to our data. Variant chr15-28260829-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 375975.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HERC2 | NM_004667.6 | c.2264T>C | p.Leu755Ser | missense_variant | 16/93 | ENST00000261609.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HERC2 | ENST00000261609.13 | c.2264T>C | p.Leu755Ser | missense_variant | 16/93 | 1 | NM_004667.6 | P1 | |
HERC2 | ENST00000564734.5 | c.*2134T>C | 3_prime_UTR_variant, NMD_transcript_variant | 17/21 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727246
GnomAD4 exome
AF:
AC:
1
AN:
1461892
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
727246
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Breast neoplasm Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Benign
T
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.0132);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at