rs2240204

Variant names:

• chr15-28248886-G-A
• rs2240204
• NM_004667.6:c.3051-150C>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.3051-150C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0897 in 648,340 control chromosomes in the GnomAD database, including 6,091 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 0.069 (880 hom., cov: 32)
  • Exomes 𝑓: 0.096 (5211 hom.)
• Consequence: HERC2 NM_004667.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0100
• Publications: 13 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 (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.3051-150C>T		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.3051-150C>T		intron_variant	Intron 20 of 92	1	NM_004667.6	ENSP00000261609.8

Frequencies

GnomAD3 genomes AF: 0.0690 AC: 10494 AN: 152134 Hom.: 885 Cov.: 32

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.0934

Gnomad ASJ AF: 0.0890

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.0563

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.0961 AC: 47666 AN: 496086 Hom.: 5211 AF XY: 0.104 AC XY: 26979 AN XY: 259484

African (AFR) AF: 0.0273 AC: 363 AN: 13302

American (AMR) AF: 0.0787 AC: 1511 AN: 19202

Ashkenazi Jewish (ASJ) AF: 0.0786 AC: 1106 AN: 14068

East Asian (EAS) AF: 0.419 AC: 13153 AN: 31376

South Asian (SAS) AF: 0.230 AC: 10207 AN: 44392

European-Finnish (FIN) AF: 0.0128 AC: 385 AN: 30086

Middle Eastern (MID) AF: 0.208 AC: 482 AN: 2316

European-Non Finnish (NFE) AF: 0.0565 AC: 17728 AN: 313612

Other (OTH) AF: 0.0985 AC: 2731 AN: 27732

GnomAD4 genome AF: 0.0689 AC: 10495 AN: 152254 Hom.: 880 Cov.: 32 AF XY: 0.0744 AC XY: 5541 AN XY: 74430

African (AFR) AF: 0.0231 AC: 958 AN: 41542

American (AMR) AF: 0.0933 AC: 1426 AN: 15290

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

East Asian (EAS) AF: 0.417 AC: 2153 AN: 5166

South Asian (SAS) AF: 0.229 AC: 1104 AN: 4814

European-Finnish (FIN) AF: 0.0133 AC: 141 AN: 10616

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.0564 AC: 3834 AN: 68036

Other (OTH) AF: 0.109 AC: 230 AN: 2112

Alfa AF: 0.0746 Hom.: 678

Bravo AF: 0.0742

Asia WGS AF: 0.265 AC: 921 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	0.082
DANN	Benign	0.66
PhyloP100		0.010
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: rs2240204; hg19: chr15-28494032;