15-28256286-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004667.6(HERC2):​c.2549C>A​(p.Pro850Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

HERC2
NM_004667.6 missense

Scores

4
7
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.53
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HERC2NM_004667.6 linkc.2549C>A p.Pro850Gln missense_variant Exon 18 of 93 ENST00000261609.13 NP_004658.3 O95714A8KAQ8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HERC2ENST00000261609.13 linkc.2549C>A p.Pro850Gln missense_variant Exon 18 of 93 1 NM_004667.6 ENSP00000261609.8 O95714
HERC2ENST00000564734.5 linkn.*2419C>A non_coding_transcript_exon_variant Exon 19 of 21 1 ENSP00000456237.1 H3BRG9
HERC2ENST00000564734.5 linkn.*2419C>A 3_prime_UTR_variant Exon 19 of 21 1 ENSP00000456237.1 H3BRG9

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152146
Hom.:
0
Cov.:
33
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1443948
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
718568
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152146
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.36
BayesDel_addAF
Uncertain
0.099
D
BayesDel_noAF
Benign
-0.10
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.38
T
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.93
D
M_CAP
Benign
0.023
T
MetaRNN
Pathogenic
0.85
D
MetaSVM
Benign
-0.68
T
MutationAssessor
Uncertain
2.3
M
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-2.0
N
REVEL
Benign
0.27
Sift
Uncertain
0.020
D
Polyphen
1.0
D
Vest4
0.89
MutPred
0.40
Gain of solvent accessibility (P = 0.0137);
MVP
0.39
MPC
1.7
ClinPred
0.98
D
GERP RS
5.3
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.8
Varity_R
0.18
gMVP
0.56

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: rs534865714; hg19: chr15-28501432; API