Genetic Variant NM_004667.6:c.7058C>G (chr15-28211013-G-C) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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. 15/21 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

Publications

3 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 -16 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 VariationId is 376985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

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.7058C>G	p.Thr2353Ser	missense	Exon 44 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.7058C>G	p.Thr2353Ser	missense	Exon 44 of 93	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

GnomAD2 exomes

AF:

0.00155

AC:

385

AN:

247628

AF XY:

0.00152

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 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

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

African (AFR)

AF:

0.00857

AC:

274

AN:

31972

American (AMR)

AF:

0.00121

AC:

AN:

44582

Ashkenazi Jewish (ASJ)

AF:

0.000425

AC:

AN:

25854

East Asian (EAS)

AF:

0.000606

AC:

AN:

39590

South Asian (SAS)

AF:

0.00211

AC:

180

AN:

85318

European-Finnish (FIN)

AF:

0.0106

AC:

564

AN:

52984

Middle Eastern (MID)

AF:

0.00147

AC:

AN:

4070

European-Non Finnish (NFE)

AF:

0.000816

AC:

881

AN:

1080176

Other (OTH)

AF:

0.00202

AC:

119

AN:

58856

⚠️ 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: 0.300

Heterozygous variant carriers

140

279

419

558

698

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00629

AC:

953

AN:

151430

Hom.:

Cov.:

AF XY:

0.00689

AC XY:

510

AN XY:

73984

show subpopulations

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

African (AFR)

AF:

0.0131

AC:

540

AN:

41166

American (AMR)

AF:

0.00315

AC:

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3466

East Asian (EAS)

AF:

0.000776

AC:

AN:

5156

South Asian (SAS)

AF:

0.00209

AC:

AN:

4788

European-Finnish (FIN)

AF:

0.0179

AC:

189

AN:

10536

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00227

AC:

154

AN:

67798

Other (OTH)

AF:

0.00285

AC:

AN:

2106

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.351

Heterozygous variant carriers

141

188

235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00352

Hom.:

ExAC

AF:

0.00363

AC:

437

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

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

PhyloP100

3.6

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

Mutation Taster

=99/1

polymorphism

(source)

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

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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