rs2240204

Positions:

• chr15-28248886-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004667.6(HERC2):​c.3051-150C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0897 in 648,340 control chromosomes in the GnomAD database, including 6,091 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 0.069 (880 hom., cov: 32)
  • Exomes 𝑓: 0.096 (5211 hom.)
• Consequence: HERC2 NM_004667.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0100

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC2	NM_004667.6	c.3051-150C>T		intron_variant		ENST00000261609.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC2	ENST00000261609.13	c.3051-150C>T		intron_variant		1	NM_004667.6	P1

Frequencies

GnomAD3 genomes AF: 0.0690 AC: 10494 AN: 152134 Hom.: 885 Cov.: 32

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.0934

Gnomad ASJ AF: 0.0890

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.0563

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.0961 AC: 47666 AN: 496086 Hom.: 5211 AF XY: 0.104 AC XY: 26979 AN XY: 259484

Gnomad4 AFR exome AF: 0.0273

Gnomad4 AMR exome AF: 0.0787

Gnomad4 ASJ exome AF: 0.0786

Gnomad4 EAS exome AF: 0.419

Gnomad4 SAS exome AF: 0.230

Gnomad4 FIN exome AF: 0.0128

Gnomad4 NFE exome AF: 0.0565

Gnomad4 OTH exome AF: 0.0985

GnomAD4 genome AF: 0.0689 AC: 10495 AN: 152254 Hom.: 880 Cov.: 32 AF XY: 0.0744 AC XY: 5541 AN XY: 74430

Gnomad4 AFR AF: 0.0231

Gnomad4 AMR AF: 0.0933

Gnomad4 ASJ AF: 0.0890

Gnomad4 EAS AF: 0.417

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.0133

Gnomad4 NFE AF: 0.0564

Gnomad4 OTH AF: 0.109

Alfa AF: 0.0669 Hom.: 349

Bravo AF: 0.0742

Asia WGS AF: 0.265 AC: 921 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.082
DANN	Benign	0.66

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

LitVar

Other links and lift over

dbSNP: rs2240204; hg19: chr15-28494032;