15-28113673-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_004667.6(HERC2):c.13919A>G(p.His4640Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00237 in 1,613,752 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (28 hom.)
• Consequence: HERC2 NM_004667.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.24

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 -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HERC2
• BP4: Computational evidence support a benign effect (MetaRNN=0.014858425).
• BP6: Variant 15-28113673-T-C is Benign according to our data. Variant chr15-28113673-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2498604.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-28113673-T-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC2	NM_004667.6	c.13919A>G	p.His4640Arg	missense_variant	91/93	ENST00000261609.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC2	ENST00000261609.13	c.13919A>G	p.His4640Arg	missense_variant	91/93	1	NM_004667.6	P1
HERC2	ENST00000566635.5	n.1044A>G		non_coding_transcript_exon_variant	5/7	1
HERC2	ENST00000562136.1	n.45A>G		non_coding_transcript_exon_variant	1/3	2
HERC2	ENST00000650509.1	c.*1033A>G		3_prime_UTR_variant, NMD_transcript_variant	37/39

Frequencies

GnomAD3 genomes AF: 0.00358 AC: 544 AN: 152160 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00523

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00339 AC: 851 AN: 251050 Hom.: 9 AF XY: 0.00333 AC XY: 452 AN XY: 135710

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0167

Gnomad NFE exome AF: 0.00394

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00224 AC: 3281 AN: 1461474 Hom.: 28 Cov.: 31 AF XY: 0.00235 AC XY: 1707 AN XY: 727096

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0161

Gnomad4 NFE exome AF: 0.00204

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00357 AC: 544 AN: 152278 Hom.: 2 Cov.: 32 AF XY: 0.00396 AC XY: 295 AN XY: 74466

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0154

Gnomad4 NFE AF: 0.00523

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00358 Hom.: 14

Bravo AF: 0.00175

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00354 AC: 430

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00202

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

HERC2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Uncertain	0.10
Cadd	Benign	23
Dann	Benign	0.96
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.026	D
Polyphen		0.99	D
Vest4		0.75
MVP		0.82
MPC		1.3
ClinPred		0.16	T
GERP RS		5.3
Varity_R		0.67
gMVP		0.66

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: rs138725743; hg19: chr15-28358819;