15-28113185-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004667.6(HERC2):c.14118G>A(p.Glu4706=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,614,122 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (34 hom.)
• Consequence: HERC2 NM_004667.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.287

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 15-28113185-C-T is Benign according to our data. Variant chr15-28113185-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 788709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-28113185-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.287 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00177 (269/152306) while in subpopulation SAS AF= 0.0083 (40/4820). AF 95% confidence interval is 0.00626. There are 2 homozygotes in gnomad4. There are 139 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• 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.14118G>A	p.Glu4706=	synonymous_variant	92/93	ENST00000261609.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC2	ENST00000261609.13	c.14118G>A	p.Glu4706=	synonymous_variant	92/93	1	NM_004667.6	P1
HERC2	ENST00000566635.5	n.1243G>A		non_coding_transcript_exon_variant	6/7	1
HERC2	ENST00000562136.1	n.244G>A		non_coding_transcript_exon_variant	2/3	2
HERC2	ENST00000650509.1	c.*1232G>A		3_prime_UTR_variant, NMD_transcript_variant	38/39

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 267 AN: 152188 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00287 AC: 721 AN: 251396 Hom.: 15 AF XY: 0.00353 AC XY: 480 AN XY: 135908

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00843

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0100

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00244 AC: 3560 AN: 1461816 Hom.: 34 Cov.: 32 AF XY: 0.00277 AC XY: 2015 AN XY: 727208

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00911

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0106

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00184

Gnomad4 OTH exome AF: 0.00323

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152306 Hom.: 2 Cov.: 32 AF XY: 0.00187 AC XY: 139 AN XY: 74470

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00196

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00245 Hom.: 0

Bravo AF: 0.00181

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00308

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	HERC2: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
Cadd	Benign	7.4
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs137918449; hg19: chr15-28358331; COSMIC: COSV55348830; COSMIC: COSV55348830;