rs8041209

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004667.6(HERC2):​c.7886-9C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,612,550 control chromosomes in the GnomAD database, including 21,469 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 6879 hom., cov: 32)
Exomes 𝑓: 0.089 ( 14590 hom. )

Consequence

HERC2
NM_004667.6 splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.0002338
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0490
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.89).
BP6
Variant 15-28198512-G-T is Benign according to our data. Variant chr15-28198512-G-T is described in ClinVar as [Benign]. Clinvar id is 1182699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HERC2NM_004667.6 linkuse as main transcriptc.7886-9C>A splice_polypyrimidine_tract_variant, intron_variant ENST00000261609.13 NP_004658.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HERC2ENST00000261609.13 linkuse as main transcriptc.7886-9C>A splice_polypyrimidine_tract_variant, intron_variant 1 NM_004667.6 ENSP00000261609 P1
HERC2ENST00000567869.1 linkuse as main transcriptn.1996-9C>A splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
AF:
0.215
AC:
32627
AN:
151964
Hom.:
6851
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.530
Gnomad AMI
AF:
0.302
Gnomad AMR
AF:
0.144
Gnomad ASJ
AF:
0.0943
Gnomad EAS
AF:
0.429
Gnomad SAS
AF:
0.236
Gnomad FIN
AF:
0.0134
Gnomad MID
AF:
0.231
Gnomad NFE
AF:
0.0573
Gnomad OTH
AF:
0.212
GnomAD3 exomes
AF:
0.143
AC:
35579
AN:
249462
Hom.:
5579
AF XY:
0.141
AC XY:
19041
AN XY:
134848
show subpopulations
Gnomad AFR exome
AF:
0.542
Gnomad AMR exome
AF:
0.0909
Gnomad ASJ exome
AF:
0.0866
Gnomad EAS exome
AF:
0.430
Gnomad SAS exome
AF:
0.232
Gnomad FIN exome
AF:
0.0116
Gnomad NFE exome
AF:
0.0616
Gnomad OTH exome
AF:
0.126
GnomAD4 exome
AF:
0.0891
AC:
130115
AN:
1460466
Hom.:
14590
Cov.:
32
AF XY:
0.0930
AC XY:
67571
AN XY:
726482
show subpopulations
Gnomad4 AFR exome
AF:
0.550
Gnomad4 AMR exome
AF:
0.0949
Gnomad4 ASJ exome
AF:
0.0845
Gnomad4 EAS exome
AF:
0.428
Gnomad4 SAS exome
AF:
0.237
Gnomad4 FIN exome
AF:
0.0127
Gnomad4 NFE exome
AF:
0.0524
Gnomad4 OTH exome
AF:
0.128
GnomAD4 genome
AF:
0.215
AC:
32705
AN:
152084
Hom.:
6879
Cov.:
32
AF XY:
0.216
AC XY:
16037
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.531
Gnomad4 AMR
AF:
0.144
Gnomad4 ASJ
AF:
0.0943
Gnomad4 EAS
AF:
0.428
Gnomad4 SAS
AF:
0.235
Gnomad4 FIN
AF:
0.0134
Gnomad4 NFE
AF:
0.0573
Gnomad4 OTH
AF:
0.211
Alfa
AF:
0.130
Hom.:
1538
Bravo
AF:
0.240
Asia WGS
AF:
0.315
AC:
1094
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxJan 10, 2020- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.89
CADD
Benign
0.35
DANN
Benign
0.29

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00023
dbscSNV1_RF
Benign
0.12
SpliceAI score (max)
0.040
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: rs8041209; hg19: chr15-28443658; COSMIC: COSV55324923; API