rs2240202

chr15-28265749-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.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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.422

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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC2	NM_004667.6	c.1757-18C>T		intron_variant		ENST00000261609.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC2	ENST00000261609.13	c.1757-18C>T		intron_variant		1	NM_004667.6	P1
HERC2	ENST00000564734.5	c.*1627-18C>T		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0671 AC: 10208 AN: 152052 Hom.: 869 Cov.: 32

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

GnomAD3 exomes AF: 0.103 AC: 25889 AN: 251272 Hom.: 2959 AF XY: 0.112 AC XY: 15244 AN XY: 135780

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 SAS exome AF: 0.231

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.: 32 AF XY: 0.0801 AC XY: 58223 AN XY: 727072

Gnomad4 AFR exome AF: 0.0162

Gnomad4 AMR exome AF: 0.0713

Gnomad4 ASJ exome AF: 0.0802

Gnomad4 EAS exome AF: 0.417

Gnomad4 SAS exome AF: 0.235

Gnomad4 FIN exome AF: 0.0131

Gnomad4 NFE exome AF: 0.0520

Gnomad4 OTH exome AF: 0.0947

GnomAD4 genome AF: 0.0670 AC: 10197 AN: 152170 Hom.: 863 Cov.: 32 AF XY: 0.0726 AC XY: 5400 AN XY: 74376

Gnomad4 AFR AF: 0.0167

Gnomad4 AMR AF: 0.0929

Gnomad4 ASJ AF: 0.0890

Gnomad4 EAS AF: 0.415

Gnomad4 SAS AF: 0.230

Gnomad4 FIN AF: 0.0133

Gnomad4 NFE AF: 0.0563

Gnomad4 OTH AF: 0.108

Alfa AF: 0.0648 Hom.: 141

Bravo AF: 0.0719

Asia WGS AF: 0.260 AC: 904 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.019
Dann	Benign	0.35

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: rs2240202; hg19: chr15-28510895; COSMIC: COSV55324937;