rs200823016

chr15-28202511-G-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BP6_Very_Strong

The NM_004667.6(HERC2):c.7316C>A(p.Ala2439Asp) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 16)
  • Exomes 𝑓: 0.0021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HERC2 NM_004667.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.77

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 -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HERC2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0035172403).
• BP6: Variant 15-28202511-G-T is Benign according to our data. Variant chr15-28202511-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 235233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC2	NM_004667.6	c.7316C>A	p.Ala2439Asp	missense_variant	46/93	ENST00000261609.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC2	ENST00000261609.13	c.7316C>A	p.Ala2439Asp	missense_variant	46/93	1	NM_004667.6	P1
HERC2	ENST00000567869.1	n.1426C>A		non_coding_transcript_exon_variant	1/10	2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 252 AN: 109510 Hom.: 0 Cov.: 16 FAILED QC

Gnomad AFR AF: 0.00782

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00263

Gnomad ASJ AF: 0.000683

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000367

Gnomad FIN AF: 0.000142

Gnomad MID AF: 0.00388

Gnomad NFE AF: 0.000396

Gnomad OTH AF: 0.00152

GnomAD3 exomes AF: 0.00150 AC: 249 AN: 166088 Hom.: 0 AF XY: 0.00133 AC XY: 118 AN XY: 88792

Gnomad AFR exome AF: 0.0220

Gnomad AMR exome AF: 0.000750

Gnomad ASJ exome AF: 0.00299

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000109

Gnomad OTH exome AF: 0.00111

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00207 AC: 2333 AN: 1126826 Hom.: 0 Cov.: 16 AF XY: 0.00178 AC XY: 1011 AN XY: 567506

Gnomad4 AFR exome AF: 0.0441

Gnomad4 AMR exome AF: 0.00131

Gnomad4 ASJ exome AF: 0.00220

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000212

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.00300

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00235 AC: 258 AN: 109580 Hom.: 0 Cov.: 16 AF XY: 0.00244 AC XY: 127 AN XY: 52004

Gnomad4 AFR AF: 0.00808

Gnomad4 AMR AF: 0.00263

Gnomad4 ASJ AF: 0.000683

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000367

Gnomad4 FIN AF: 0.000142

Gnomad4 NFE AF: 0.000396

Gnomad4 OTH AF: 0.00150

Alfa AF: 0.00288 Hom.: 0

ExAC AF: 0.00282 AC: 324

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	HERC2: PP2, BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 25, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.65	D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.13
Sift	Benign	0.60	T
Polyphen		0.0010	B
Vest4		0.24
MVP		0.15
MPC		1.1
ClinPred		0.074	T
GERP RS		4.0
Varity_R		0.13
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200823016; hg19: chr15-28447657; COSMIC: COSV55349728;