2-196201240-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001348768.2(HECW2):c.*37G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.712 in 1,329,794 control chromosomes in the GnomAD database, including 338,595 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.68 (35244 hom., cov: 32)
  • Exomes 𝑓: 0.72 (303351 hom.)
• Consequence: HECW2 NM_001348768.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0260

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-196201240-C-A is Benign according to our data. Variant chr2-196201240-C-A is described in ClinVar as [Benign]. Clinvar id is 1285331.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HECW2	NM_001348768.2	c.*37G>T		3_prime_UTR_variant	29/29	ENST00000644978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HECW2	ENST00000644978.2	c.*37G>T		3_prime_UTR_variant	29/29		NM_001348768.2	P1

Frequencies

GnomAD3 genomes AF: 0.677 AC: 102883 AN: 151936 Hom.: 35218 Cov.: 32

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.696

Gnomad AMR AF: 0.715

Gnomad ASJ AF: 0.684

Gnomad EAS AF: 0.832

Gnomad SAS AF: 0.748

Gnomad FIN AF: 0.733

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.685

GnomAD3 exomes AF: 0.721 AC: 180561 AN: 250384 Hom.: 65478 AF XY: 0.723 AC XY: 97847 AN XY: 135318

Gnomad AFR exome AF: 0.569

Gnomad AMR exome AF: 0.753

Gnomad ASJ exome AF: 0.688

Gnomad EAS exome AF: 0.835

Gnomad SAS exome AF: 0.754

Gnomad FIN exome AF: 0.728

Gnomad NFE exome AF: 0.708

Gnomad OTH exome AF: 0.714

GnomAD4 exome AF: 0.716 AC: 843778 AN: 1177740 Hom.: 303351 Cov.: 16 AF XY: 0.717 AC XY: 429906 AN XY: 599328

Gnomad4 AFR exome AF: 0.561

Gnomad4 AMR exome AF: 0.752

Gnomad4 ASJ exome AF: 0.687

Gnomad4 EAS exome AF: 0.855

Gnomad4 SAS exome AF: 0.753

Gnomad4 FIN exome AF: 0.725

Gnomad4 NFE exome AF: 0.711

Gnomad4 OTH exome AF: 0.717

GnomAD4 genome AF: 0.677 AC: 102951 AN: 152054 Hom.: 35244 Cov.: 32 AF XY: 0.679 AC XY: 50495 AN XY: 74330

Gnomad4 AFR AF: 0.568

Gnomad4 AMR AF: 0.715

Gnomad4 ASJ AF: 0.684

Gnomad4 EAS AF: 0.832

Gnomad4 SAS AF: 0.748

Gnomad4 FIN AF: 0.733

Gnomad4 NFE AF: 0.709

Gnomad4 OTH AF: 0.684

Alfa AF: 0.698 Hom.: 37250

Bravo AF: 0.672

Asia WGS AF: 0.755 AC: 2627 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with hypotonia, seizures, and absent language Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.90
Dann	Benign	0.54

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: rs3820908; hg19: chr2-197065964;