15-28168546-G-C

Variant names:

• chr15-28168546-G-C
• rs147705404
• NM_004667.6:c.10274C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004667.6(HERC2):​c.10274C>G​(p.Pro3425Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3425L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HERC2 NM_004667.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.79
• Publications: 4 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC2	NM_004667.6	c.10274C>G	p.Pro3425Arg	missense_variant	Exon 67 of 93	ENST00000261609.13	NP_004658.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC2	ENST00000261609.13	c.10274C>G	p.Pro3425Arg	missense_variant	Exon 67 of 93	1	NM_004667.6	ENSP00000261609.8
HERC2	ENST00000569772.1	c.245C>G	p.Pro82Arg	missense_variant	Exon 3 of 5	5		ENSP00000457745.1
HERC2	ENST00000650509.1	n.1985C>G		non_coding_transcript_exon_variant	Exon 15 of 39			ENSP00000496936.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250886 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.052
Eigen_PC	Benign	-0.060
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.24
Sift	Benign	0.24	T
Vest4		0.57
ClinPred		0.89	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.13
gMVP		0.40

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: rs147705404; hg19: chr15-28413692;