rs200823016

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_004667.6(HERC2):c.7316C>A(p.Ala2439Asp) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 16)

Exomes 𝑓: 0.0021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HERC2
NM_004667.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 9.77

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]

HERC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035172403).

BP6

Variant 15-28202511-G-T is Benign according to our data. Variant chr15-28202511-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 235233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC2	NM_004667.6 link	c.7316C>A	p.Ala2439Asp	missense_variant	Exon 46 of 93	ENST00000261609.13	NP_004658.3	O95714A8KAQ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC2	ENST00000261609.13 link	c.7316C>A	p.Ala2439Asp	missense_variant	Exon 46 of 93	1	NM_004667.6	ENSP00000261609.8		O95714
HERC2	ENST00000567869.1 link	n.1426C>A		non_coding_transcript_exon_variant	Exon 1 of 10	2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

252

AN:

109510

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00782

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00263

Gnomad ASJ

AF:

0.000683

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000367

Gnomad FIN

AF:

0.000142

Gnomad MID

AF:

0.00388

Gnomad NFE

AF:

0.000396

Gnomad OTH

AF:

0.00152

GnomAD3 exomes

AF:

0.00150

AC:

249

AN:

166088

Hom.:

AF XY:

0.00133

AC XY:

118

AN XY:

88792

show subpopulations

Gnomad AFR exome

AF:

0.0220

Gnomad AMR exome

AF:

0.000750

Gnomad ASJ exome

AF:

0.00299

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000210

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000109

Gnomad OTH exome

AF:

0.00111

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00207

AC:

2333

AN:

1126826

Hom.:

Cov.:

AF XY:

0.00178

AC XY:

1011

AN XY:

567506

show subpopulations

Gnomad4 AFR exome

AF:

0.0441

Gnomad4 AMR exome

AF:

0.00131

Gnomad4 ASJ exome

AF:

0.00220

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000212

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00114

Gnomad4 OTH exome

AF:

0.00300

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00235

AC:

258

AN:

109580

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

127

AN XY:

52004

show subpopulations

Gnomad4 AFR

AF:

0.00808

Gnomad4 AMR

AF:

0.00263

Gnomad4 ASJ

AF:

0.000683

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000367

Gnomad4 FIN

AF:

0.000142

Gnomad4 NFE

AF:

0.000396

Gnomad4 OTH

AF:

0.00150

Alfa

AF:

0.00288

Hom.:

ExAC

AF:

0.00282

AC:

324

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HERC2: PP2, BP4, BS1 -

Jul 06, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 25, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.19

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.5

REVEL

Benign

0.13

Sift

Benign

0.60

Polyphen

0.0010

Vest4

0.24

MVP

0.15

MPC

1.1

ClinPred

0.074

GERP RS

4.0

Varity_R

0.13

gMVP

0.22

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over