rs8028689

Variant names:

• chr15-28243742-T-C
• rs8028689
• NM_004667.6:c.3577+2139A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004667.6(HERC2):​c.3577+2139A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 152,088 control chromosomes in the GnomAD database, including 3,401 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 0.16 (3401 hom., cov: 32)
• Consequence: HERC2 NM_004667.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.14
• Publications: 42 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC2	NM_004667.6	c.3577+2139A>G		intron_variant	Intron 23 of 92	ENST00000261609.13	NP_004658.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC2	ENST00000261609.13	c.3577+2139A>G		intron_variant	Intron 23 of 92	1	NM_004667.6	ENSP00000261609.8

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24372 AN: 151970 Hom.: 3385 Cov.: 32

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.0926

Gnomad EAS AF: 0.430

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.0572

Gnomad OTH AF: 0.171

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

GnomAD4 genome AF: 0.161 AC: 24438 AN: 152088 Hom.: 3401 Cov.: 32 AF XY: 0.164 AC XY: 12168 AN XY: 74380

African (AFR) AF: 0.342 AC: 14177 AN: 41448

American (AMR) AF: 0.122 AC: 1868 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0926 AC: 321 AN: 3466

East Asian (EAS) AF: 0.429 AC: 2215 AN: 5158

South Asian (SAS) AF: 0.233 AC: 1119 AN: 4806

European-Finnish (FIN) AF: 0.0135 AC: 143 AN: 10618

Middle Eastern (MID) AF: 0.236 AC: 69 AN: 292

European-Non Finnish (NFE) AF: 0.0572 AC: 3892 AN: 67990

Other (OTH) AF: 0.170 AC: 359 AN: 2112

Alfa AF: 0.0995 Hom.: 6422

Bravo AF: 0.179

Asia WGS AF: 0.293 AC: 1020 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.41
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8028689; hg19: chr15-28488888;