chr15-28208069-A-G

Variant names:

• chr15-28208069-A-G
• rs2238289
• NM_004667.6:c.7070-1687T>C

Variant summary

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

The NM_004667.6(HERC2):​c.7070-1687T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 152,094 control chromosomes in the GnomAD database, including 12,061 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 0.32 (12061 hom., cov: 32)
• Consequence: HERC2 NM_004667.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40
• Publications: 17 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.706 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.7070-1687T>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.7070-1687T>C		intron	N/A	ENSP00000261609.8	O95714

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48886 AN: 151976 Hom.: 12023 Cov.: 32

Gnomad AFR AF: 0.631

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.725

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.349

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

GnomAD4 genome AF: 0.322 AC: 48985 AN: 152094 Hom.: 12061 Cov.: 32 AF XY: 0.326 AC XY: 24240 AN XY: 74378

African (AFR) AF: 0.632 AC: 26167 AN: 41426

American (AMR) AF: 0.372 AC: 5675 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 802 AN: 3466

East Asian (EAS) AF: 0.725 AC: 3759 AN: 5182

South Asian (SAS) AF: 0.436 AC: 2098 AN: 4816

European-Finnish (FIN) AF: 0.0325 AC: 345 AN: 10616

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9034 AN: 68012

Other (OTH) AF: 0.345 AC: 730 AN: 2114

Alfa AF: 0.223 Hom.: 869

Bravo AF: 0.362

Asia WGS AF: 0.531 AC: 1842 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.028
DANN	Benign	0.44
PhyloP100		-1.4
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: rs2238289; hg19: chr15-28453215;