rs11636232

chr15-28141480-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_004667.6(HERC2):c.11967G>A(p.Gln3989=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,613,722 control chromosomes in the GnomAD database, including 110,194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (7247 hom., cov: 31)
  • Exomes 𝑓: 0.35 (102947 hom.)
• Consequence: HERC2 NM_004667.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.859

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 15-28141480-C-T is Benign according to our data. Variant chr15-28141480-C-T is described in ClinVar as [Benign]. Clinvar id is 1224285.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.859 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC2	NM_004667.6	c.11967G>A	p.Gln3989=	synonymous_variant	78/93	ENST00000261609.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC2	ENST00000261609.13	c.11967G>A	p.Gln3989=	synonymous_variant	78/93	1	NM_004667.6	P1
HERC2	ENST00000650509.1	c.3678G>A	p.Gln1226=	synonymous_variant, NMD_transcript_variant	26/39

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37948 AN: 151960 Hom.: 7247 Cov.: 31

Gnomad AFR AF: 0.0670

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0261

Gnomad FIN AF: 0.492

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.156

GnomAD3 exomes AF: 0.249 AC: 62555 AN: 251456 Hom.: 12422 AF XY: 0.245 AC XY: 33275 AN XY: 135902

Gnomad AFR exome AF: 0.0624

Gnomad AMR exome AF: 0.0696

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0262

Gnomad FIN exome AF: 0.497

Gnomad NFE exome AF: 0.389

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.346 AC: 506003 AN: 1461644 Hom.: 102947 Cov.: 44 AF XY: 0.336 AC XY: 244364 AN XY: 727142

Gnomad4 AFR exome AF: 0.0522

Gnomad4 AMR exome AF: 0.0749

Gnomad4 ASJ exome AF: 0.172

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0285

Gnomad4 FIN exome AF: 0.503

Gnomad4 NFE exome AF: 0.405

Gnomad4 OTH exome AF: 0.283

GnomAD4 genome AF: 0.249 AC: 37942 AN: 152078 Hom.: 7247 Cov.: 31 AF XY: 0.243 AC XY: 18069 AN XY: 74326

Gnomad4 AFR AF: 0.0668

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0261

Gnomad4 FIN AF: 0.492

Gnomad4 NFE AF: 0.398

Gnomad4 OTH AF: 0.155

Alfa AF: 0.322 Hom.: 14137

Bravo AF: 0.213

Asia WGS AF: 0.0240 AC: 84 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	2.3
Dann	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs11636232; hg19: chr15-28386626;