Genetic Variant NM_004667.6:c.1757-18C>T (chr15-28265749-G-A) – 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.1757-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0734 in 1,613,686 control chromosomes in the GnomAD database, including 9,595 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 0.067 ( 863 hom., cov: 32)

Exomes 𝑓: 0.074 ( 8732 hom. )

Consequence

HERC2
NM_004667.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.422

Publications

14 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:

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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=-0.83).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.4 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.1757-18C>T		intron	N/A	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.1757-18C>T		intron	N/A	ENSP00000261609.8	O95714
	HERC2	ENST00000564734.5	TSL:1	n.*1627-18C>T		intron	N/A	ENSP00000456237.1	H3BRG9

Frequencies

GnomAD3 genomes

AF:

0.0671

AC:

10208

AN:

152052

Hom.:

869

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0167

Gnomad AMI

AF:

0.302

Gnomad AMR

AF:

0.0930

Gnomad ASJ

AF:

0.0890

Gnomad EAS

AF:

0.415

Gnomad SAS

AF:

0.231

Gnomad FIN

AF:

0.0133

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.0563

Gnomad OTH

AF:

0.109

GnomAD2 exomes

AF:

0.103

AC:

25889

AN:

251272

AF XY:

0.112

show subpopulations

Gnomad AFR exome

AF:

0.0132

Gnomad AMR exome

AF:

0.0698

Gnomad ASJ exome

AF:

0.0823

Gnomad EAS exome

AF:

0.411

Gnomad FIN exome

AF:

0.0120

Gnomad NFE exome

AF:

0.0606

Gnomad OTH exome

AF:

0.109

GnomAD4 exome

AF:

0.0740

AC:

108177

AN:

1461516

Hom.:

8732

Cov.:

AF XY:

0.0801

AC XY:

58223

AN XY:

727072

show subpopulations

African (AFR)

AF:

0.0162

AC:

542

AN:

33478

American (AMR)

AF:

0.0713

AC:

3191

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0802

AC:

2096

AN:

26136

East Asian (EAS)

AF:

0.417

AC:

16548

AN:

39694

South Asian (SAS)

AF:

0.235

AC:

20254

AN:

86248

European-Finnish (FIN)

AF:

0.0131

AC:

699

AN:

53420

Middle Eastern (MID)

AF:

0.221

AC:

1271

AN:

5762

European-Non Finnish (NFE)

AF:

0.0520

AC:

57858

AN:

1111676

Other (OTH)

AF:

0.0947

AC:

5718

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

5826

11653

17479

23306

29132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2324

4648

6972

9296

11620

<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:

0.0670

AC:

10197

AN:

152170

Hom.:

863

Cov.:

AF XY:

0.0726

AC XY:

5400

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0167

AC:

693

AN:

41534

American (AMR)

AF:

0.0929

AC:

1419

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0890

AC:

309

AN:

3470

East Asian (EAS)

AF:

0.415

AC:

2130

AN:

5138

South Asian (SAS)

AF:

0.230

AC:

1106

AN:

4812

European-Finnish (FIN)

AF:

0.0133

AC:

141

AN:

10608

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0563

AC:

3831

AN:

68018

Other (OTH)

AF:

0.108

AC:

228

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

450

900

1351

1801

2251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<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:

0.0640

Hom.:

210

Bravo

AF:

0.0719

Asia WGS

AF:

0.260

AC:

904

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.019

(source)

DANN

Benign

0.35

PhyloP100

-0.42

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

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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