rs12592730

Variant names:

• chr15-28285213-G-A
• rs12592730
• NM_004667.6:c.323-4926C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-28285213-G-A
• chr15-28285213-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004667.6(HERC2):​c.323-4926C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0672 in 152,154 control chromosomes in the GnomAD database, including 864 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 (864 hom., cov: 32)
• Consequence: HERC2 NM_004667.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04
• Publications: 10 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC2	NM_004667.6	c.323-4926C>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.323-4926C>T		intron_variant	Intron 4 of 92	1	NM_004667.6	ENSP00000261609.8
HERC2	ENST00000564734.5	n.*193-4926C>T		intron_variant	Intron 5 of 20	1		ENSP00000456237.1
HERC2	ENST00000564383.1	n.218-4926C>T		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0673 AC: 10232 AN: 152036 Hom.: 870 Cov.: 32

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.0933

Gnomad ASJ AF: 0.0890

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.0564

Gnomad OTH AF: 0.108

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

GnomAD4 genome AF: 0.0672 AC: 10221 AN: 152154 Hom.: 864 Cov.: 32 AF XY: 0.0728 AC XY: 5415 AN XY: 74372

African (AFR) AF: 0.0167 AC: 693 AN: 41548

American (AMR) AF: 0.0932 AC: 1423 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0890 AC: 309 AN: 3472

East Asian (EAS) AF: 0.416 AC: 2149 AN: 5162

South Asian (SAS) AF: 0.230 AC: 1107 AN: 4812

European-Finnish (FIN) AF: 0.0132 AC: 140 AN: 10572

Middle Eastern (MID) AF: 0.223 AC: 65 AN: 292

European-Non Finnish (NFE) AF: 0.0564 AC: 3835 AN: 68014

Other (OTH) AF: 0.108 AC: 227 AN: 2108

Alfa AF: 0.0744 Hom.: 550

Bravo AF: 0.0720

Asia WGS AF: 0.262 AC: 911 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
DANN	Benign	0.46
PhyloP100		-1.0
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: rs12592730; hg19: chr15-28530359;