Genetic Variant HERC2:p.Val2532Met (chr15-28202136-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004667.6(HERC2):c.7594G>A(p.Val2532Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,519,884 control chromosomes in the GnomAD database, including 6,251 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 3844 hom., cov: 28)

Exomes 𝑓: 0.011 ( 2407 hom. )

Consequence

HERC2
NM_004667.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.172

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

developmental delay with autism spectrum disorder and gait instability
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

HERC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.5486173E-5).

BP6

Variant 15-28202136-C-T is Benign according to our data. Variant chr15-28202136-C-T is described in ClinVar as Benign. ClinVar VariationId is 402930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004667.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC2	NM_004667.6	MANE Select	c.7594G>A	p.Val2532Met	missense	Exon 47 of 93	NP_004658.3	O95714

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC2	ENST00000261609.13	TSL:1 MANE Select	c.7594G>A	p.Val2532Met	missense	Exon 47 of 93	ENSP00000261609.8	O95714
	HERC2	ENST00000567869.1	TSL:2	n.1704G>A		non_coding_transcript_exon	Exon 2 of 10

Frequencies

GnomAD3 genomes

AF:

0.126

AC:

18406

AN:

145816

Hom.:

3830

Cov.:

show subpopulations

Gnomad AFR

AF:

0.445

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0454

Gnomad ASJ

AF:

0.00552

Gnomad EAS

AF:

0.0153

Gnomad SAS

AF:

0.00283

Gnomad FIN

AF:

0.000297

Gnomad MID

AF:

0.0128

Gnomad NFE

AF:

0.00114

Gnomad OTH

AF:

0.0902

GnomAD2 exomes

AF:

0.0328

AC:

5848

AN:

178500

AF XY:

0.0256

show subpopulations

Gnomad AFR exome

AF:

0.467

Gnomad AMR exome

AF:

0.0217

Gnomad ASJ exome

AF:

0.00424

Gnomad EAS exome

AF:

0.0211

Gnomad FIN exome

AF:

0.000474

Gnomad NFE exome

AF:

0.00103

Gnomad OTH exome

AF:

0.0157

GnomAD4 exome

AF:

0.0108

AC:

14832

AN:

1373966

Hom.:

2407

Cov.:

AF XY:

0.00923

AC XY:

6332

AN XY:

686326

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.424

AC:

11342

AN:

26780

American (AMR)

AF:

0.0209

AC:

827

AN:

39528

Ashkenazi Jewish (ASJ)

AF:

0.00378

AC:

AN:

25398

East Asian (EAS)

AF:

0.0191

AC:

491

AN:

25744

South Asian (SAS)

AF:

0.00162

AC:

134

AN:

82750

European-Finnish (FIN)

AF:

0.0000776

AC:

AN:

51528

Middle Eastern (MID)

AF:

0.0119

AC:

AN:

4788

European-Non Finnish (NFE)

AF:

0.000399

AC:

423

AN:

1061304

Other (OTH)

AF:

0.0260

AC:

1458

AN:

56146

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

425

851

1276

1702

2127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

278

556

834

1112

1390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.127

AC:

18464

AN:

145918

Hom.:

3844

Cov.:

AF XY:

0.123

AC XY:

8719

AN XY:

70998

show subpopulations

African (AFR)

AF:

0.445

AC:

17475

AN:

39248

American (AMR)

AF:

0.0454

AC:

633

AN:

13950

Ashkenazi Jewish (ASJ)

AF:

0.00552

AC:

AN:

3440

East Asian (EAS)

AF:

0.0154

AC:

AN:

3898

South Asian (SAS)

AF:

0.00283

AC:

AN:

4590

European-Finnish (FIN)

AF:

0.000297

AC:

AN:

10088

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00114

AC:

AN:

67476

Other (OTH)

AF:

0.0893

AC:

181

AN:

2026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

451

903

1354

1806

2257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

154

308

462

616

770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0106

Hom.:

Bravo

AF:

0.144

ExAC

AF:

0.0367

AC:

4368

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.20

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.069

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.074

LIST_S2

Benign

0.23

MetaRNN

Benign

0.000025

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

PhyloP100

-0.17

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.11

REVEL

Benign

0.0080

Sift

Benign

0.23

Polyphen

0.0020

Vest4

0.16

MPC

0.75

ClinPred

0.0025

GERP RS

-4.4

Varity_R

0.017

gMVP

0.13

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over