Genetic Variant HERC2:c.1084-70G>A (chr15-28270938-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004667.6(HERC2):c.1084-70G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.776 in 1,370,128 control chromosomes in the GnomAD database, including 438,843 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.65 ( 37311 hom., cov: 33)

Exomes 𝑓: 0.79 ( 401532 hom. )

Consequence

HERC2
NM_004667.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.302

Publications

18 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

HERC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC2	NM_004667.6 link	c.1084-70G>A		intron_variant	Intron 9 of 92	ENST00000261609.13	NP_004658.3	O95714A8KAQ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC2	ENST00000261609.13 link	c.1084-70G>A		intron_variant	Intron 9 of 92	1	NM_004667.6	ENSP00000261609.8		O95714
HERC2	ENST00000564734.5 link	n.*954-70G>A		intron_variant	Intron 10 of 20	1		ENSP00000456237.1		H3BRG9

Frequencies

GnomAD3 genomes

AF:

0.649

AC:

98690

AN:

151986

Hom.:

37319

Cov.:

show subpopulations

Gnomad AFR

AF:

0.298

Gnomad AMI

AF:

0.666

Gnomad AMR

AF:

0.610

Gnomad ASJ

AF:

0.763

Gnomad EAS

AF:

0.266

Gnomad SAS

AF:

0.427

Gnomad FIN

AF:

0.969

Gnomad MID

AF:

0.598

Gnomad NFE

AF:

0.862

Gnomad OTH

AF:

0.621

GnomAD4 exome

AF:

0.792

AC:

964831

AN:

1218024

Hom.:

401532

AF XY:

0.782

AC XY:

477529

AN XY:

610762

show subpopulations

African (AFR)

AF:

0.277

AC:

7810

AN:

28174

American (AMR)

AF:

0.597

AC:

21066

AN:

35290

Ashkenazi Jewish (ASJ)

AF:

0.772

AC:

18051

AN:

23370

East Asian (EAS)

AF:

0.255

AC:

9167

AN:

36016

South Asian (SAS)

AF:

0.432

AC:

32203

AN:

74564

European-Finnish (FIN)

AF:

0.967

AC:

48354

AN:

49990

Middle Eastern (MID)

AF:

0.572

AC:

2106

AN:

3680

European-Non Finnish (NFE)

AF:

0.862

AC:

788169

AN:

914852

Other (OTH)

AF:

0.728

AC:

37905

AN:

52088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

8502

17004

25505

34007

42509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16228

32456

48684

64912

81140

<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:

0.649

AC:

98686

AN:

152104

Hom.:

37311

Cov.:

AF XY:

0.644

AC XY:

47898

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.298

AC:

12332

AN:

41448

American (AMR)

AF:

0.610

AC:

9319

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.763

AC:

2647

AN:

3470

East Asian (EAS)

AF:

0.266

AC:

1370

AN:

5158

South Asian (SAS)

AF:

0.427

AC:

2056

AN:

4810

European-Finnish (FIN)

AF:

0.969

AC:

10294

AN:

10622

Middle Eastern (MID)

AF:

0.595

AC:

175

AN:

294

European-Non Finnish (NFE)

AF:

0.862

AC:

58583

AN:

67998

Other (OTH)

AF:

0.617

AC:

1304

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1262

2524

3785

5047

6309

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

736

1472

2208

2944

3680

<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:

0.766

Hom.:

31621

Bravo

AF:

0.609

Asia WGS

AF:

0.389

AC:

1353

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

6.5

(source)

DANN

Benign

0.38

PhyloP100

0.30

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over