rs8041209

Variant names:

• chr15-28198512-G-T
• rs8041209
• NM_004667.6:c.7886-9C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004667.6(HERC2):​c.7886-9C>A variant causes a 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 intron
• Scores: Splicing: ADA: 0.0002338
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0490
• Publications: 18 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1182699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.525 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.7886-9C>A		intron	N/A	NP_004658.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC2	ENST00000261609.13	TSL:1 MANE Select	c.7886-9C>A		intron	N/A	ENSP00000261609.8
	HERC2	ENST00000567869.1	TSL:2	n.1996-9C>A		intron	N/A

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

GnomAD2 exomes AF: 0.143 AC: 35579 AN: 249462 AF XY: 0.141

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 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

African (AFR) AF: 0.550 AC: 18342 AN: 33340

American (AMR) AF: 0.0949 AC: 4218 AN: 44432

Ashkenazi Jewish (ASJ) AF: 0.0845 AC: 2204 AN: 26082

East Asian (EAS) AF: 0.428 AC: 17002 AN: 39688

South Asian (SAS) AF: 0.237 AC: 20303 AN: 85830

European-Finnish (FIN) AF: 0.0127 AC: 677 AN: 53412

Middle Eastern (MID) AF: 0.243 AC: 1392 AN: 5740

European-Non Finnish (NFE) AF: 0.0524 AC: 58257 AN: 1111620

Other (OTH) AF: 0.128 AC: 7720 AN: 60322

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

African (AFR) AF: 0.531 AC: 22013 AN: 41434

American (AMR) AF: 0.144 AC: 2194 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0943 AC: 327 AN: 3468

East Asian (EAS) AF: 0.428 AC: 2211 AN: 5168

South Asian (SAS) AF: 0.235 AC: 1131 AN: 4820

European-Finnish (FIN) AF: 0.0134 AC: 142 AN: 10608

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.0573 AC: 3898 AN: 67988

Other (OTH) AF: 0.211 AC: 445 AN: 2110

Alfa AF: 0.130 Hom.: 1538

Bravo AF: 0.240

Asia WGS AF: 0.315 AC: 1094 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.35
DANN	Benign	0.29
PhyloP100		0.049
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8041209; hg19: chr15-28443658; COSMIC: COSV55324923;