Genetic Variant HERC2:p.Val2532Leu (chr15-28202136-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004667.6(HERC2):c.7594G>C(p.Val2532Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2532M) has been classified as Benign.

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HERC2
NM_004667.6 missense

Scores

Clinical Significance

Not reported in ClinVar

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

HERC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.019537061).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC2	NM_004667.6 link	c.7594G>C	p.Val2532Leu	missense_variant	Exon 47 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.7594G>C	p.Val2532Leu	missense_variant	Exon 47 of 93	1	NM_004667.6	ENSP00000261609.8		O95714
HERC2	ENST00000567869.1 link	n.1704G>C		non_coding_transcript_exon_variant	Exon 2 of 10	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000560

AC:

AN:

178500

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000145

AC:

AN:

1383542

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

691030

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27762

American (AMR)

AF:

0.00

AC:

AN:

40492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25480

East Asian (EAS)

AF:

0.00

AC:

AN:

31132

South Asian (SAS)

AF:

0.00

AC:

AN:

83106

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4804

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1062298

Other (OTH)

AF:

0.0000353

AC:

AN:

56656

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ExAC

AF:

0.00000840

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.036

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.067

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.22

M_CAP

Benign

0.014

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.11

PhyloP100

-0.17

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.11

REVEL

Benign

0.027

Sift

Benign

0.67

Polyphen

0.0

Vest4

0.17

MutPred

0.15

Loss of sheet (P = 0.1907);

MVP

0.14

MPC

0.72

ClinPred

0.0082

GERP RS

-4.4

Varity_R

0.017

gMVP

0.12

Mutation Taster

=100/0

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over