rs16950987

Variant names:

• chr15-28281082-G-A
• rs16950987
• NM_004667.6:c.323-795C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 16 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 -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 rank	MANE	Protein	UniProt
HERC2	NM_004667.6	c.323-795C>T		intron_variant	Intron 4 of 92	ENST00000261609.13	NP_004658.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC2	ENST00000261609.13	c.323-795C>T		intron_variant	Intron 4 of 92	1	NM_004667.6	ENSP00000261609.8
HERC2	ENST00000564734.5	n.*193-795C>T		intron_variant	Intron 5 of 20	1		ENSP00000456237.1
HERC2	ENST00000564383.1	n.218-795C>T		intron_variant	Intron 2 of 2	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

African (AFR) AF: 0.571 AC: 23667 AN: 41428

American (AMR) AF: 0.146 AC: 2229 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0945 AC: 328 AN: 3472

East Asian (EAS) AF: 0.426 AC: 2196 AN: 5158

South Asian (SAS) AF: 0.232 AC: 1117 AN: 4808

European-Finnish (FIN) AF: 0.0134 AC: 142 AN: 10588

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.0576 AC: 3917 AN: 67974

Other (OTH) AF: 0.219 AC: 462 AN: 2114

Alfa AF: 0.115 Hom.: 1465

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
PhyloP100		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16950987; hg19: chr15-28526228;