2-196215918-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001348768.2(HECW2):c.4554C>T(p.Asn1518=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00777 in 1,613,780 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (57 hom.)
• Consequence: HECW2 NM_001348768.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.553

Genes affected

HECW2 (HGNC:29853): (HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2) This gene encodes a member of a family of E3 ubiquitin ligases which plays an important role in the proliferation, migration and differentiation of neural crest cells as a regulator of glial cell line-derived neurotrophic factor (GDNF)/Ret signaling. This gene also plays an important role in angiogenesis through stabilization of endothelial cell-to-cell junctions as a regulator of angiomotin-like 1 stability. The encoded protein contains an N-terminal calcium/lipid-binding (C2) domain involved in membrane targeting, two-four WW domains responsible for cellular localization and substrate recognition, and a C-terminal homologous with E6-associated protein C-terminus (HECT) catalytic domain. Naturally occurring mutations in this gene are associated with neurodevelopmental delay, hypotonia, and epilepsy. The decreased expression of this gene in the aganglionic colon is associated with Hirschsprung's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-196215918-G-A is Benign according to our data. Variant chr2-196215918-G-A is described in ClinVar as [Benign]. Clinvar id is 708316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.553 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00518 (789/152276) while in subpopulation NFE AF= 0.00831 (565/68024). AF 95% confidence interval is 0.00774. There are 3 homozygotes in gnomad4. There are 362 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 789 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HECW2	NM_001348768.2	c.4554C>T	p.Asn1518=	synonymous_variant	28/29	ENST00000644978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HECW2	ENST00000644978.2	c.4554C>T	p.Asn1518=	synonymous_variant	28/29		NM_001348768.2	P1

Frequencies

GnomAD3 genomes AF: 0.00519 AC: 789 AN: 152158 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00933

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00830

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00580 AC: 1457 AN: 251402 Hom.: 7 AF XY: 0.00575 AC XY: 781 AN XY: 135868

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00268

Gnomad FIN exome AF: 0.00896

Gnomad NFE exome AF: 0.00861

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00804 AC: 11745 AN: 1461504 Hom.: 57 Cov.: 30 AF XY: 0.00799 AC XY: 5807 AN XY: 727076

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00314

Gnomad4 FIN exome AF: 0.0100

Gnomad4 NFE exome AF: 0.00917

Gnomad4 OTH exome AF: 0.00621

GnomAD4 genome AF: 0.00518 AC: 789 AN: 152276 Hom.: 3 Cov.: 32 AF XY: 0.00486 AC XY: 362 AN XY: 74462

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00933

Gnomad4 NFE AF: 0.00831

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00739 Hom.: 5

Bravo AF: 0.00476

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00807

EpiControl AF: 0.00782

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	HECW2: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 27, 2019	- -

HECW2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	3.8
Dann	Benign	0.81

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: rs17310196; hg19: chr2-197080642; COSMIC: COSV53675305;