rs16950987

chr15-28281082-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.323-795C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 152,030 control chromosomes in the GnomAD database, including 7,790 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 0.23 (7790 hom., cov: 32)
• Consequence: HERC2 NM_004667.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.153

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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC2	NM_004667.6	c.323-795C>T		intron_variant		ENST00000261609.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC2	ENST00000261609.13	c.323-795C>T		intron_variant		1	NM_004667.6	P1
HERC2	ENST00000564734.5	c.*193-795C>T		intron_variant, NMD_transcript_variant		1
HERC2	ENST00000564383.1	n.218-795C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34315 AN: 151912 Hom.: 7757 Cov.: 32

Gnomad AFR AF: 0.571

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.0945

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.0576

Gnomad OTH AF: 0.220

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

GnomAD4 genome AF: 0.226 AC: 34401 AN: 152030 Hom.: 7790 Cov.: 32 AF XY: 0.226 AC XY: 16806 AN XY: 74322

Gnomad4 AFR AF: 0.571

Gnomad4 AMR AF: 0.146

Gnomad4 ASJ AF: 0.0945

Gnomad4 EAS AF: 0.426

Gnomad4 SAS AF: 0.232

Gnomad4 FIN AF: 0.0134

Gnomad4 NFE AF: 0.0576

Gnomad4 OTH AF: 0.219

Alfa AF: 0.106 Hom.: 1144

Bravo AF: 0.252

Asia WGS AF: 0.303 AC: 1054 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
Cadd	Benign	2.4
Dann	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs16950987; hg19: chr15-28526228;