rs145370046

Positions:

chr15-28211013-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004667.6(HERC2):c.7058C>G(p.Thr2353Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00629 in 151,430 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 6 hom., cov: 30)

Exomes 𝑓: 0.0015 ( 10 hom. )

Failed GnomAD Quality Control

Consequence

HERC2
NM_004667.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.62

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038871765).

BP6

Variant 15-28211013-G-C is Benign according to our data. Variant chr15-28211013-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 376985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-28211013-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00629 (953/151430) while in subpopulation AFR AF= 0.0131 (540/41166). AF 95% confidence interval is 0.0122. There are 6 homozygotes in gnomad4. There are 510 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HERC2	NM_004667.6 link	c.7058C>G	p.Thr2353Ser	missense_variant	44/93	ENST00000261609.13	NP_004658.3	O95714A8KAQ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HERC2	ENST00000261609.13 link	c.7058C>G	p.Thr2353Ser	missense_variant	44/93	1	NM_004667.6	ENSP00000261609.8		O95714

Frequencies

GnomAD3 genomes

AF:

0.00628

AC:

951

AN:

151322

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00309

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.000774

Gnomad SAS

AF:

0.00209

Gnomad FIN

AF:

0.0179

Gnomad MID

AF:

0.00323

Gnomad NFE

AF:

0.00227

Gnomad OTH

AF:

0.00288

GnomAD3 exomes

AF:

0.00155

AC:

385

AN:

247628

Hom.:

AF XY:

0.00152

AC XY:

204

AN XY:

134342

show subpopulations

Gnomad AFR exome

AF:

0.00746

Gnomad AMR exome

AF:

0.000609

Gnomad ASJ exome

AF:

0.000201

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.00134

Gnomad FIN exome

AF:

0.00411

Gnomad NFE exome

AF:

0.00100

Gnomad OTH exome

AF:

0.000826

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00148

AC:

2113

AN:

1423402

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1054

AN XY:

710048

show subpopulations

Gnomad4 AFR exome

AF:

0.00857

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.000425

Gnomad4 EAS exome

AF:

0.000606

Gnomad4 SAS exome

AF:

0.00211

Gnomad4 FIN exome

AF:

0.0106

Gnomad4 NFE exome

AF:

0.000816

Gnomad4 OTH exome

AF:

0.00202

GnomAD4 genome

AF:

0.00629

AC:

953

AN:

151430

Hom.:

Cov.:

AF XY:

0.00689

AC XY:

510

AN XY:

73984

show subpopulations

Gnomad4 AFR

AF:

0.0131

Gnomad4 AMR

AF:

0.00315

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.000776

Gnomad4 SAS

AF:

0.00209

Gnomad4 FIN

AF:

0.0179

Gnomad4 NFE

AF:

0.00227

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.00352

Hom.:

ExAC

AF:

0.00363

AC:

437

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	HERC2: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 23, 2017	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 05, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.18

DEOGEN2

Benign

0.050

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.70

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0039

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.10

REVEL

Benign

0.058

Sift

Benign

1.0

Polyphen

0.0

Vest4

0.066

MutPred

0.17

Loss of glycosylation at T2353 (P = 0.0182);

MVP

0.23

MPC

0.65

ClinPred

0.0098

GERP RS

2.5

Varity_R

0.036

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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