rs6497292

Variant names:

• chr15-28251049-A-G
• rs6497292
• NM_004667.6:c.3051-2313T>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.3051-2313T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 152,156 control chromosomes in the GnomAD database, including 7,433 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 0.22 (7433 hom., cov: 32)
• Consequence: HERC2 NM_004667.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.278
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC2	NM_004667.6	c.3051-2313T>C		intron_variant	Intron 20 of 92	ENST00000261609.13	NP_004658.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC2	ENST00000261609.13	c.3051-2313T>C		intron_variant	Intron 20 of 92	1	NM_004667.6	ENSP00000261609.8

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33623 AN: 152038 Hom.: 7402 Cov.: 32

Gnomad AFR AF: 0.554

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0945

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.0576

Gnomad OTH AF: 0.215

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

GnomAD4 genome AF: 0.222 AC: 33708 AN: 152156 Hom.: 7433 Cov.: 32 AF XY: 0.222 AC XY: 16484 AN XY: 74402

African (AFR) AF: 0.555 AC: 22988 AN: 41454

American (AMR) AF: 0.145 AC: 2211 AN: 15292

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

East Asian (EAS) AF: 0.426 AC: 2207 AN: 5176

South Asian (SAS) AF: 0.232 AC: 1117 AN: 4810

European-Finnish (FIN) AF: 0.0134 AC: 142 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0576 AC: 3920 AN: 68016

Other (OTH) AF: 0.214 AC: 452 AN: 2112

Alfa AF: 0.161 Hom.: 1022

Bravo AF: 0.247

Asia WGS AF: 0.301 AC: 1047 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.0
DANN	Benign	0.38
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6497292; hg19: chr15-28496195;