NM_004667.6:c.13188+214G>A

Variant names:

• chr15-28123823-C-T
• rs11635884
• NM_004667.6:c.13188+214G>A

Variant summary

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

The NM_004667.6(HERC2):​c.13188+214G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.849 in 152,242 control chromosomes in the GnomAD database, including 58,356 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 0.85 (58356 hom., cov: 33)
• Consequence: HERC2 NM_004667.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.570
• Publications: 7 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 (NFE) allele frequency at 95% confidence interval = 0.987 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.13188+214G>A		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.13188+214G>A		intron	N/A	ENSP00000261609.8
	HERC2	ENST00000650509.1		n.*302+214G>A		intron	N/A	ENSP00000496936.1

Frequencies

GnomAD3 genomes AF: 0.850 AC: 129289 AN: 152124 Hom.: 58356 Cov.: 33

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.980

Gnomad AMR AF: 0.941

Gnomad ASJ AF: 0.969

Gnomad EAS AF: 0.979

Gnomad SAS AF: 0.863

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.993

Gnomad OTH AF: 0.877

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

GnomAD4 genome AF: 0.849 AC: 129320 AN: 152242 Hom.: 58356 Cov.: 33 AF XY: 0.853 AC XY: 63482 AN XY: 74454

African (AFR) AF: 0.510 AC: 21148 AN: 41478

American (AMR) AF: 0.941 AC: 14409 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.969 AC: 3363 AN: 3472

East Asian (EAS) AF: 0.980 AC: 5070 AN: 5176

South Asian (SAS) AF: 0.862 AC: 4158 AN: 4822

European-Finnish (FIN) AF: 1.00 AC: 10620 AN: 10624

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.993 AC: 67557 AN: 68038

Other (OTH) AF: 0.871 AC: 1842 AN: 2114

Alfa AF: 0.941 Hom.: 40826

Bravo AF: 0.833

Asia WGS AF: 0.876 AC: 3042 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.63
DANN	Benign	0.17
PhyloP100		-0.57
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: rs11635884; hg19: chr15-28368969;