15-28256286-G-C

Variant names:

• chr15-28256286-G-C
• rs534865714
• NM_004667.6:c.2549C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_004667.6(HERC2):​c.2549C>G​(p.Pro850Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000009 in 1,443,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: HERC2 NM_004667.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.53

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 Uncertain_significance. Variant got 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC2	NM_004667.6	c.2549C>G	p.Pro850Arg	missense_variant	Exon 18 of 93	ENST00000261609.13	NP_004658.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC2	ENST00000261609.13	c.2549C>G	p.Pro850Arg	missense_variant	Exon 18 of 93	1	NM_004667.6	ENSP00000261609.8
HERC2	ENST00000564734.5	n.*2419C>G		non_coding_transcript_exon_variant	Exon 19 of 21	1		ENSP00000456237.1
HERC2	ENST00000564734.5	n.*2419C>G		3_prime_UTR_variant	Exon 19 of 21	1		ENSP00000456237.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000216 AC: 5 AN: 231998 Hom.: 0 AF XY: 0.0000315 AC XY: 4 AN XY: 126992

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000900 AC: 13 AN: 1443948 Hom.: 0 Cov.: 32 AF XY: 0.0000167 AC XY: 12 AN XY: 718568

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000152

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000166 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.48		Loss of loop (P = 0.0203);
MVP		0.58
MPC		1.8
ClinPred		0.68	D
GERP RS		5.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.32
gMVP		0.69

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: rs534865714; hg19: chr15-28501432;