rs2240202

Variant names:

• chr15-28265749-G-A
• rs2240202
• NM_004667.6:c.1757-18C>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.1757-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0734 in 1,613,686 control chromosomes in the GnomAD database, including 9,595 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 (863 hom., cov: 32)
  • Exomes 𝑓: 0.074 (8732 hom.)
• Consequence: HERC2 NM_004667.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.422
• Publications: 14 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004667.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC2	NM_004667.6	MANE Select	c.1757-18C>T		intron	N/A	NP_004658.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC2	ENST00000261609.13	TSL:1 MANE Select	c.1757-18C>T		intron	N/A	ENSP00000261609.8
	HERC2	ENST00000564734.5	TSL:1	n.*1627-18C>T		intron	N/A	ENSP00000456237.1

Frequencies

GnomAD3 genomes AF: 0.0671 AC: 10208 AN: 152052 Hom.: 869 Cov.: 32

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.0930

Gnomad ASJ AF: 0.0890

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.0563

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.103 AC: 25889 AN: 251272 AF XY: 0.112

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.0698

Gnomad ASJ exome AF: 0.0823

Gnomad EAS exome AF: 0.411

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.0606

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.0740 AC: 108177 AN: 1461516 Hom.: 8732 Cov.: 32 AF XY: 0.0801 AC XY: 58223 AN XY: 727072

African (AFR) AF: 0.0162 AC: 542 AN: 33478

American (AMR) AF: 0.0713 AC: 3191 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0802 AC: 2096 AN: 26136

East Asian (EAS) AF: 0.417 AC: 16548 AN: 39694

South Asian (SAS) AF: 0.235 AC: 20254 AN: 86248

European-Finnish (FIN) AF: 0.0131 AC: 699 AN: 53420

Middle Eastern (MID) AF: 0.221 AC: 1271 AN: 5762

European-Non Finnish (NFE) AF: 0.0520 AC: 57858 AN: 1111676

Other (OTH) AF: 0.0947 AC: 5718 AN: 60378

GnomAD4 genome AF: 0.0670 AC: 10197 AN: 152170 Hom.: 863 Cov.: 32 AF XY: 0.0726 AC XY: 5400 AN XY: 74376

African (AFR) AF: 0.0167 AC: 693 AN: 41534

American (AMR) AF: 0.0929 AC: 1419 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0890 AC: 309 AN: 3470

East Asian (EAS) AF: 0.415 AC: 2130 AN: 5138

South Asian (SAS) AF: 0.230 AC: 1106 AN: 4812

European-Finnish (FIN) AF: 0.0133 AC: 141 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0563 AC: 3831 AN: 68018

Other (OTH) AF: 0.108 AC: 228 AN: 2104

Alfa AF: 0.0640 Hom.: 210

Bravo AF: 0.0719

Asia WGS AF: 0.260 AC: 904 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.019
DANN	Benign	0.35
PhyloP100		-0.42
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: rs2240202; hg19: chr15-28510895; COSMIC: COSV55324937;