rs11636232

Variant names:

• chr15-28141480-C-T
• rs11636232
• NM_004667.6:c.11967G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004667.6(HERC2):​c.11967G>A​(p.Gln3989Gln) 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.859
• Publications: 28 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 -19 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 VariationId is 1224285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
HERC2	NM_004667.6	c.11967G>A	p.Gln3989Gln	synonymous_variant	Exon 78 of 93	ENST00000261609.13	NP_004658.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC2	ENST00000261609.13	c.11967G>A	p.Gln3989Gln	synonymous_variant	Exon 78 of 93	1	NM_004667.6	ENSP00000261609.8
HERC2	ENST00000650509.1	n.3678G>A		non_coding_transcript_exon_variant	Exon 26 of 39			ENSP00000496936.1

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

GnomAD2 exomes AF: 0.249 AC: 62555 AN: 251456 AF XY: 0.245

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 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

African (AFR) AF: 0.0522 AC: 1747 AN: 33480

American (AMR) AF: 0.0749 AC: 3348 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 4491 AN: 26136

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39700

South Asian (SAS) AF: 0.0285 AC: 2455 AN: 86258

European-Finnish (FIN) AF: 0.503 AC: 26896 AN: 53420

Middle Eastern (MID) AF: 0.0201 AC: 116 AN: 5766

European-Non Finnish (NFE) AF: 0.405 AC: 449833 AN: 1111778

Other (OTH) AF: 0.283 AC: 17105 AN: 60382

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

African (AFR) AF: 0.0668 AC: 2773 AN: 41528

American (AMR) AF: 0.108 AC: 1656 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 582 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.0261 AC: 126 AN: 4824

European-Finnish (FIN) AF: 0.492 AC: 5196 AN: 10560

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.398 AC: 27007 AN: 67938

Other (OTH) AF: 0.155 AC: 326 AN: 2106

Alfa AF: 0.308 Hom.: 17333

Bravo AF: 0.213

Asia WGS AF: 0.0240 AC: 84 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

May 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	2.3
DANN	Benign	0.50
PhyloP100		0.86
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: rs11636232; hg19: chr15-28386626; COSMIC: COSV108018622; COSMIC: COSV108018622;