15-28123823-C-T

Position:

• chr15-28123823-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC2	NM_004667.6	c.13188+214G>A		intron_variant		ENST00000261609.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC2	ENST00000261609.13	c.13188+214G>A		intron_variant		1	NM_004667.6	P1
HERC2	ENST00000650509.1	c.*302+214G>A		intron_variant, NMD_transcript_variant

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

Gnomad4 AFR AF: 0.510

Gnomad4 AMR AF: 0.941

Gnomad4 ASJ AF: 0.969

Gnomad4 EAS AF: 0.980

Gnomad4 SAS AF: 0.862

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.993

Gnomad4 OTH AF: 0.871

Alfa AF: 0.949 Hom.: 34565

Bravo AF: 0.833

Asia WGS AF: 0.876 AC: 3042 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.63
DANN	Benign	0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs11635884; hg19: chr15-28368969;