chr15-28277538-T-C

Variant names:

• chr15-28277538-T-C
• rs2346050
• NM_004667.6:c.542+2530A>G

Variant summary

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

The NM_004667.6(HERC2):​c.542+2530A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 151,784 control chromosomes in the GnomAD database, including 7,873 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 (7873 hom., cov: 31)
• Consequence: HERC2 NM_004667.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.277
• 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC2	NM_004667.6	c.542+2530A>G		intron_variant	Intron 5 of 92	ENST00000261609.13	NP_004658.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC2	ENST00000261609.13	c.542+2530A>G		intron_variant	Intron 5 of 92	1	NM_004667.6	ENSP00000261609.8
HERC2	ENST00000564734.5	n.*412+2530A>G		intron_variant	Intron 6 of 20	1		ENSP00000456237.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34412 AN: 151676 Hom.: 7841 Cov.: 31

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.0946

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.0576

Gnomad OTH AF: 0.222

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

GnomAD4 genome AF: 0.227 AC: 34498 AN: 151784 Hom.: 7873 Cov.: 31 AF XY: 0.227 AC XY: 16865 AN XY: 74156

African (AFR) AF: 0.575 AC: 23760 AN: 41354

American (AMR) AF: 0.147 AC: 2235 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0946 AC: 328 AN: 3468

East Asian (EAS) AF: 0.426 AC: 2196 AN: 5154

South Asian (SAS) AF: 0.232 AC: 1116 AN: 4804

European-Finnish (FIN) AF: 0.0136 AC: 142 AN: 10472

Middle Eastern (MID) AF: 0.236 AC: 68 AN: 288

European-Non Finnish (NFE) AF: 0.0576 AC: 3915 AN: 67978

Other (OTH) AF: 0.220 AC: 463 AN: 2100

Alfa AF: 0.146 Hom.: 833

Bravo AF: 0.253

Asia WGS AF: 0.305 AC: 1059 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.6
DANN	Benign	0.68
PhyloP100		0.28
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: rs2346050; hg19: chr15-28522684;