2-196288535-G-A

Position:

• chr2-196288535-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001348768.2(HECW2):​c.3000+4030C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.633 in 152,060 control chromosomes in the GnomAD database, including 34,521 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 0.63 (34516 hom., cov: 31)
  • Exomes 𝑓: 0.92 (5 hom.)
• Consequence: HECW2 NM_001348768.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.985

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HECW2	NM_001348768.2	c.3000+4030C>T		intron_variant		ENST00000644978.2	NP_001335697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HECW2	ENST00000644978.2	c.3000+4030C>T		intron_variant			NM_001348768.2	ENSP00000495418	P1

Frequencies

GnomAD3 genomes AF: 0.633 AC: 96231 AN: 151930 Hom.: 34514 Cov.: 31

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.870

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.724

Gnomad EAS AF: 0.948

Gnomad SAS AF: 0.669

Gnomad FIN AF: 0.803

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.762

Gnomad OTH AF: 0.664

GnomAD4 exome AF: 0.917 AC: 11 AN: 12 Hom.: 5 Cov.: 0 AF XY: 1.00 AC XY: 8 AN XY: 8

Gnomad4 NFE exome AF: 0.900

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.633 AC: 96246 AN: 152048 Hom.: 34516 Cov.: 31 AF XY: 0.639 AC XY: 47485 AN XY: 74344

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.759

Gnomad4 ASJ AF: 0.724

Gnomad4 EAS AF: 0.948

Gnomad4 SAS AF: 0.670

Gnomad4 FIN AF: 0.803

Gnomad4 NFE AF: 0.762

Gnomad4 OTH AF: 0.663

Alfa AF: 0.738 Hom.: 55408

Bravo AF: 0.617

Asia WGS AF: 0.774 AC: 2691 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.2
DANN	Benign	0.53

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: rs4850695; hg19: chr2-197153259;