rs8041209

chr15-28198512-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004667.6(HERC2):c.7886-9C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,612,550 control chromosomes in the GnomAD database, including 21,469 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (6879 hom., cov: 32)
  • Exomes 𝑓: 0.089 (14590 hom.)
• Consequence: HERC2 NM_004667.6 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002338
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0490

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 15-28198512-G-T is Benign according to our data. Variant chr15-28198512-G-T is described in ClinVar as [Benign]. Clinvar id is 1182699.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC2	NM_004667.6	c.7886-9C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000261609.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC2	ENST00000261609.13	c.7886-9C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004667.6	P1
HERC2	ENST00000567869.1	n.1996-9C>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32627 AN: 151964 Hom.: 6851 Cov.: 32

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.0943

Gnomad EAS AF: 0.429

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.0573

Gnomad OTH AF: 0.212

GnomAD3 exomes AF: 0.143 AC: 35579 AN: 249462 Hom.: 5579 AF XY: 0.141 AC XY: 19041 AN XY: 134848

Gnomad AFR exome AF: 0.542

Gnomad AMR exome AF: 0.0909

Gnomad ASJ exome AF: 0.0866

Gnomad EAS exome AF: 0.430

Gnomad SAS exome AF: 0.232

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.0616

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.0891 AC: 130115 AN: 1460466 Hom.: 14590 Cov.: 32 AF XY: 0.0930 AC XY: 67571 AN XY: 726482

Gnomad4 AFR exome AF: 0.550

Gnomad4 AMR exome AF: 0.0949

Gnomad4 ASJ exome AF: 0.0845

Gnomad4 EAS exome AF: 0.428

Gnomad4 SAS exome AF: 0.237

Gnomad4 FIN exome AF: 0.0127

Gnomad4 NFE exome AF: 0.0524

Gnomad4 OTH exome AF: 0.128

GnomAD4 genome AF: 0.215 AC: 32705 AN: 152084 Hom.: 6879 Cov.: 32 AF XY: 0.216 AC XY: 16037 AN XY: 74360

Gnomad4 AFR AF: 0.531

Gnomad4 AMR AF: 0.144

Gnomad4 ASJ AF: 0.0943

Gnomad4 EAS AF: 0.428

Gnomad4 SAS AF: 0.235

Gnomad4 FIN AF: 0.0134

Gnomad4 NFE AF: 0.0573

Gnomad4 OTH AF: 0.211

Alfa AF: 0.130 Hom.: 1538

Bravo AF: 0.240

Asia WGS AF: 0.315 AC: 1094 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.35
Dann	Benign	0.29

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00023
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.040		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: rs8041209; hg19: chr15-28443658; COSMIC: COSV55324923;