15-28113185-C-T

Position:

chr15-28113185-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.287

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC2	NM_004667.6 linkuse as main transcript	c.14118G>A	p.Glu4706=	synonymous_variant	92/93	ENST00000261609.13

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.00175

AC:

267

AN:

152188

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00353

AC XY:

480

AN XY:

135908

show subpopulations

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.:

Cov.:

AF XY:

0.00277

AC XY:

2015

AN XY:

727208

show subpopulations

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.:

Cov.:

AF XY:

0.00187

AC XY:

139

AN XY:

74470

show subpopulations

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.:

Bravo

AF:

0.00181

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00322

EpiControl

AF:

0.00308

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	HERC2: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

HERC2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over