2-196193138-C-T

Variant names:

• chr2-196193138-C-T
• rs13001220
• ENST00000642884.1:n.133+2134G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000642884.1(HECW2):​n.133+2134G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.667 in 151,980 control chromosomes in the GnomAD database, including 35,273 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.67 (35273 hom., cov: 31)
• Consequence: HECW2 ENST00000642884.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.14
• Publications: 2 publications found

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]

HECW2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD, AR Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
• neurodevelopmental disorder with hypotonia, seizures, and absent language

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.81 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HECW2	ENST00000642884.1	n.133+2134G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101364 AN: 151862 Hom.: 35245 Cov.: 31

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.729

Gnomad AMR AF: 0.715

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.831

Gnomad SAS AF: 0.752

Gnomad FIN AF: 0.778

Gnomad MID AF: 0.656

Gnomad NFE AF: 0.746

Gnomad OTH AF: 0.677

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.667 AC: 101437 AN: 151980 Hom.: 35273 Cov.: 31 AF XY: 0.670 AC XY: 49820 AN XY: 74304

African (AFR) AF: 0.458 AC: 18973 AN: 41412

American (AMR) AF: 0.716 AC: 10931 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2434 AN: 3468

East Asian (EAS) AF: 0.830 AC: 4291 AN: 5168

South Asian (SAS) AF: 0.752 AC: 3621 AN: 4814

European-Finnish (FIN) AF: 0.778 AC: 8235 AN: 10588

Middle Eastern (MID) AF: 0.664 AC: 194 AN: 292

European-Non Finnish (NFE) AF: 0.746 AC: 50672 AN: 67950

Other (OTH) AF: 0.676 AC: 1423 AN: 2106

Alfa AF: 0.726 Hom.: 20172

Bravo AF: 0.653

Asia WGS AF: 0.766 AC: 2664 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0020
DANN	Benign	0.41
PhyloP100		-4.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs13001220; hg19: chr2-197057862;