dbSNP rs12913832: HERC2:c.13272+874T>C (chr15-28120472-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is . The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_004667.6(HERC2):c.13272+874T>C variant causes a intron change. The variant allele was found at a frequency of 0.487 in 152,216 control chromosomes in the GnomAD database, including 26,125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

Frequency

Genomes: 𝑓 0.49 ( 26125 hom., cov: 33)

Consequence

HERC2
NM_004667.6 intron

Scores

Clinical Significance

association no assertion criteria provided O:1

Conservation

PhyloP100: 3.94

Publications

341 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: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

HERC2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_004667.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.758 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.13272+874T>C		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.13272+874T>C		intron	N/A	ENSP00000261609.8	O95714
	HERC2	ENST00000650509.1		n.*386+874T>C		intron	N/A	ENSP00000496936.1	A0A3B3IRP6

Frequencies

GnomAD3 genomes

AF:

0.487

AC:

74071

AN:

152098

Hom.:

26131

Cov.:

show subpopulations

Gnomad AFR

AF:

0.126

Gnomad AMI

AF:

0.623

Gnomad AMR

AF:

0.243

Gnomad ASJ

AF:

0.572

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0911

Gnomad FIN

AF:

0.885

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.764

Gnomad OTH

AF:

0.350

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.487

AC:

74054

AN:

152216

Hom.:

26125

Cov.:

AF XY:

0.474

AC XY:

35273

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.126

AC:

5236

AN:

41528

American (AMR)

AF:

0.243

AC:

3715

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.572

AC:

1986

AN:

3472

East Asian (EAS)

AF:

0.00174

AC:

AN:

5182

South Asian (SAS)

AF:

0.0910

AC:

439

AN:

4826

European-Finnish (FIN)

AF:

0.885

AC:

9400

AN:

10616

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.764

AC:

51909

AN:

67982

Other (OTH)

AF:

0.346

AC:

730

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1186

2372

3558

4744

5930

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

576

1152

1728

2304

2880

<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:

0.635

Hom.:

131866

Bravo

AF:

0.423

Asia WGS

AF:

0.0650

AC:

229

AN:

3478

ClinVar

ClinVar submissions

Significance:association

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.68

PhyloP100

3.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over