rs756835034

Variant names:

• chr15-28272968-TC-T
• rs756835034
• NM_004667.6:c.836delG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 10P and 2B. PVS1 PM2 BP6_Moderate

The NM_004667.6(HERC2):​c.836delG​(p.Gly279GlufsTer25) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HERC2 NM_004667.6 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.95
• Publications: 10 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 15-28272968-TC-T is Benign according to our data. Variant chr15-28272968-TC-T is described in ClinVar as Benign. ClinVar VariationId is 402931.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004667.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC2	NM_004667.6	MANE Select	c.836delG	p.Gly279GlufsTer25	frameshift	Exon 8 of 93	NP_004658.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC2	ENST00000261609.13	TSL:1 MANE Select	c.836delG	p.Gly279GlufsTer25	frameshift	Exon 8 of 93	ENSP00000261609.8
	HERC2	ENST00000564734.5	TSL:1	n.*706delG		non_coding_transcript_exon	Exon 9 of 21	ENSP00000456237.1
	HERC2	ENST00000564734.5	TSL:1	n.*706delG		3_prime_UTR	Exon 9 of 21	ENSP00000456237.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00569 AC: 1068 AN: 187752 AF XY: 0.00532

Gnomad AFR exome AF: 0.00616

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.00948

Gnomad EAS exome AF: 0.00449

Gnomad FIN exome AF: 0.00334

Gnomad NFE exome AF: 0.00333

Gnomad OTH exome AF: 0.00610

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.178 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=6/194	disease causing (fs/PTC)

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: rs756835034; hg19: chr15-28518114; COSMIC: COSV55306091;