Variant chr2-196306451-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001348768.2(HECW2):c.2814+37G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.748 in 1,567,756 control chromosomes in the GnomAD database, including 441,951 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 38882 hom., cov: 31)

Exomes 𝑓: 0.75 ( 403069 hom. )

Consequence

HECW2
NM_001348768.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.721

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 2-196306451-C-T is Benign according to our data. Variant chr2-196306451-C-T is described in ClinVar as [Benign]. Clinvar id is 1285333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.945 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HECW2	NM_001348768.2 linkuse as main transcript	c.2814+37G>A		intron_variant		ENST00000644978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HECW2	ENST00000644978.2 linkuse as main transcript	c.2814+37G>A		intron_variant			NM_001348768.2	P1	Q9P2P5-1

Frequencies

GnomAD3 genomes

AF:

0.707

AC:

107269

AN:

151730

Hom.:

38865

Cov.:

show subpopulations

Gnomad AFR

AF:

0.544

Gnomad AMI

AF:

0.824

Gnomad AMR

AF:

0.790

Gnomad ASJ

AF:

0.768

Gnomad EAS

AF:

0.968

Gnomad SAS

AF:

0.754

Gnomad FIN

AF:

0.776

Gnomad MID

AF:

0.671

Gnomad NFE

AF:

0.749

Gnomad OTH

AF:

0.729

GnomAD3 exomes

AF:

0.766

AC:

171977

AN:

224648

Hom.:

66914

AF XY:

0.764

AC XY:

92843

AN XY:

121560

show subpopulations

Gnomad AFR exome

AF:

0.530

Gnomad AMR exome

AF:

0.846

Gnomad ASJ exome

AF:

0.763

Gnomad EAS exome

AF:

0.978

Gnomad SAS exome

AF:

0.751

Gnomad FIN exome

AF:

0.782

Gnomad NFE exome

AF:

0.745

Gnomad OTH exome

AF:

0.748

GnomAD4 exome

AF:

0.752

AC:

1065335

AN:

1415908

Hom.:

403069

Cov.:

AF XY:

0.753

AC XY:

528890

AN XY:

702416

show subpopulations

Gnomad4 AFR exome

AF:

0.526

Gnomad4 AMR exome

AF:

0.837

Gnomad4 ASJ exome

AF:

0.761

Gnomad4 EAS exome

AF:

0.954

Gnomad4 SAS exome

AF:

0.748

Gnomad4 FIN exome

AF:

0.775

Gnomad4 NFE exome

AF:

0.748

Gnomad4 OTH exome

AF:

0.753

GnomAD4 genome

AF:

0.707

AC:

107338

AN:

151848

Hom.:

38882

Cov.:

AF XY:

0.711

AC XY:

52790

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.544

Gnomad4 AMR

AF:

0.790

Gnomad4 ASJ

AF:

0.768

Gnomad4 EAS

AF:

0.967

Gnomad4 SAS

AF:

0.754

Gnomad4 FIN

AF:

0.776

Gnomad4 NFE

AF:

0.749

Gnomad4 OTH

AF:

0.729

Alfa

AF:

0.727

Hom.:

7829

Bravo

AF:

0.702

Asia WGS

AF:

0.833

AC:

2893

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.049

DANN

Benign

0.67

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over