rs1350102

chr2-196298078-A-G

Variant summary

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

The NM_001348768.2(HECW2):c.2815-5328T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0699 in 152,278 control chromosomes in the GnomAD database, including 427 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 0.070 (427 hom., cov: 32)
• Consequence: HECW2 NM_001348768.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.122

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=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HECW2	NM_001348768.2	c.2815-5328T>C		intron_variant		ENST00000644978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HECW2	ENST00000644978.2	c.2815-5328T>C		intron_variant			NM_001348768.2	P1

Frequencies

GnomAD3 genomes AF: 0.0700 AC: 10656 AN: 152160 Hom.: 429 Cov.: 32

Gnomad AFR AF: 0.0525

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.0592

Gnomad ASJ AF: 0.0749

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0427

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0794

Gnomad OTH AF: 0.0627

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

GnomAD4 genome AF: 0.0699 AC: 10651 AN: 152278 Hom.: 427 Cov.: 32 AF XY: 0.0693 AC XY: 5161 AN XY: 74462

Gnomad4 AFR AF: 0.0523

Gnomad4 AMR AF: 0.0591

Gnomad4 ASJ AF: 0.0749

Gnomad4 EAS AF: 0.135

Gnomad4 SAS AF: 0.109

Gnomad4 FIN AF: 0.0427

Gnomad4 NFE AF: 0.0794

Gnomad4 OTH AF: 0.0626

Alfa AF: 0.0774 Hom.: 234

Bravo AF: 0.0697

Asia WGS AF: 0.0940 AC: 325 AN: 3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	4.1
Dann	Benign	0.62

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: rs1350102; hg19: chr2-197162802;