15-28202136-C-T

Variant names:

• chr15-28202136-C-T
• rs74005645
• NM_004667.6:c.7594G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004667.6(HERC2):​c.7594G>A​(p.Val2532Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,519,884 control chromosomes in the GnomAD database, including 6,251 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (3844 hom., cov: 28)
  • Exomes 𝑓: 0.011 (2407 hom.)
• Consequence: HERC2 NM_004667.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.172
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• developmental delay with autism spectrum disorder and gait instability

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.5486173E-5).
• BP6: Variant 15-28202136-C-T is Benign according to our data. Variant chr15-28202136-C-T is described in ClinVar as Benign. ClinVar VariationId is 402930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC2	NM_004667.6	c.7594G>A	p.Val2532Met	missense_variant	Exon 47 of 93	ENST00000261609.13	NP_004658.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC2	ENST00000261609.13	c.7594G>A	p.Val2532Met	missense_variant	Exon 47 of 93	1	NM_004667.6	ENSP00000261609.8
HERC2	ENST00000567869.1	n.1704G>A		non_coding_transcript_exon_variant	Exon 2 of 10	2

Frequencies

GnomAD3 genomes AF: 0.126 AC: 18406 AN: 145816 Hom.: 3830 Cov.: 28

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0454

Gnomad ASJ AF: 0.00552

Gnomad EAS AF: 0.0153

Gnomad SAS AF: 0.00283

Gnomad FIN AF: 0.000297

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.00114

Gnomad OTH AF: 0.0902

GnomAD2 exomes AF: 0.0328 AC: 5848 AN: 178500 AF XY: 0.0256

Gnomad AFR exome AF: 0.467

Gnomad AMR exome AF: 0.0217

Gnomad ASJ exome AF: 0.00424

Gnomad EAS exome AF: 0.0211

Gnomad FIN exome AF: 0.000474

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0108 AC: 14832 AN: 1373966 Hom.: 2407 Cov.: 24 AF XY: 0.00923 AC XY: 6332 AN XY: 686326

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.424 AC: 11342 AN: 26780

American (AMR) AF: 0.0209 AC: 827 AN: 39528

Ashkenazi Jewish (ASJ) AF: 0.00378 AC: 96 AN: 25398

East Asian (EAS) AF: 0.0191 AC: 491 AN: 25744

South Asian (SAS) AF: 0.00162 AC: 134 AN: 82750

European-Finnish (FIN) AF: 0.0000776 AC: 4 AN: 51528

Middle Eastern (MID) AF: 0.0119 AC: 57 AN: 4788

European-Non Finnish (NFE) AF: 0.000399 AC: 423 AN: 1061304

Other (OTH) AF: 0.0260 AC: 1458 AN: 56146

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.127 AC: 18464 AN: 145918 Hom.: 3844 Cov.: 28 AF XY: 0.123 AC XY: 8719 AN XY: 70998

African (AFR) AF: 0.445 AC: 17475 AN: 39248

American (AMR) AF: 0.0454 AC: 633 AN: 13950

Ashkenazi Jewish (ASJ) AF: 0.00552 AC: 19 AN: 3440

East Asian (EAS) AF: 0.0154 AC: 60 AN: 3898

South Asian (SAS) AF: 0.00283 AC: 13 AN: 4590

European-Finnish (FIN) AF: 0.000297 AC: 3 AN: 10088

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 290

European-Non Finnish (NFE) AF: 0.00114 AC: 77 AN: 67476

Other (OTH) AF: 0.0893 AC: 181 AN: 2026

Alfa AF: 0.0106 Hom.: 38

Bravo AF: 0.144

ExAC AF: 0.0367 AC: 4368

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 06, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.20
DANN	Benign	0.79
DEOGEN2	Benign	0.069	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.000025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.17
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.0080
Sift	Benign	0.23	T
Polyphen		0.0020	B
Vest4		0.16
MPC		0.75
ClinPred		0.0025	T
GERP RS		-4.4
Varity_R		0.017
gMVP		0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs74005645; hg19: chr15-28447282; COSMIC: COSV55323711;