rs200823016

Positions:

• 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:4
• 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]

HERC2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HERC2. . Gene score misZ 4.4237 (greater than the threshold 3.09). Trascript score misZ 7.8111 (greater than threshold 3.09). GenCC has associacion of gene with developmental delay with autism spectrum disorder and gait instability.
• 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	Protein	UniProt
HERC2	NM_004667.6	c.7316C>A	p.Ala2439Asp	missense_variant	46/93	ENST00000261609.13	NP_004658.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HERC2	ENST00000261609.13	c.7316C>A	p.Ala2439Asp	missense_variant	46/93	1	NM_004667.6	ENSP00000261609.8
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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	HERC2: PP2, BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 25, 2016	- -

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
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;