2-196394265-C-T

Position:

• chr2-196394265-C-T

Variant summary

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

The NM_001348768.2(HECW2):​c.292+38867G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 151,970 control chromosomes in the GnomAD database, including 29,292 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 0.58 (29292 hom., cov: 31)
• Consequence: HECW2 NM_001348768.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.818 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HECW2	NM_001348768.2	c.292+38867G>A		intron_variant		ENST00000644978.2	NP_001335697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HECW2	ENST00000644978.2	c.292+38867G>A		intron_variant			NM_001348768.2	ENSP00000495418.1

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88766 AN: 151852 Hom.: 29289 Cov.: 31

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.721

Gnomad ASJ AF: 0.652

Gnomad EAS AF: 0.838

Gnomad SAS AF: 0.565

Gnomad FIN AF: 0.787

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.695

Gnomad OTH AF: 0.619

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

GnomAD4 genome AF: 0.584 AC: 88787 AN: 151970 Hom.: 29292 Cov.: 31 AF XY: 0.591 AC XY: 43909 AN XY: 74280

Gnomad4 AFR AF: 0.260

Gnomad4 AMR AF: 0.722

Gnomad4 ASJ AF: 0.652

Gnomad4 EAS AF: 0.838

Gnomad4 SAS AF: 0.565

Gnomad4 FIN AF: 0.787

Gnomad4 NFE AF: 0.695

Gnomad4 OTH AF: 0.619

Alfa AF: 0.640 Hom.: 4138

Bravo AF: 0.567

Asia WGS AF: 0.683 AC: 2377 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	0.53
DANN	Benign	0.72

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: rs4850704; hg19: chr2-197258989;