2-196215882-T-A

Position:

chr2-196215882-T-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BS1_SupportingBS2

The NM_001348768.2(HECW2):c.4590A>T(p.Lys1530Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000823 in 1,458,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

HECW2
NM_001348768.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.657

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:

HECW2 (HGNC:):

HECW2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HECW2. . Gene score misZ 3.3052 (greater than the threshold 3.09). Trascript score misZ 3.6429 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with hypotonia, seizures, and absent language, complex neurodevelopmental disorder.

BP4

Computational evidence support a benign effect (MetaRNN=0.3632151).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000823 (12/1458952) while in subpopulation MID AF= 0.000693 (4/5768). AF 95% confidence interval is 0.000236. There are 0 homozygotes in gnomad4_exome. There are 8 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HECW2	NM_001348768.2 linkuse as main transcript	c.4590A>T	p.Lys1530Asn	missense_variant	28/29	ENST00000644978.2	NP_001335697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HECW2	ENST00000644978.2 linkuse as main transcript	c.4590A>T	p.Lys1530Asn	missense_variant	28/29		NM_001348768.2	ENSP00000495418.1		Q9P2P5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251320

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00000823

AC:

AN:

1458952

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726064

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000631

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.000334

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;.;T;T

Eigen

Benign

-0.044

Eigen_PC

Benign

-0.069

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.94

.;D;.;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.36

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.4

L;.;L;L

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-4.4

D;.;.;.

REVEL

Benign

0.27

Sift

Uncertain

0.0090

D;.;.;.

Sift4G

Uncertain

0.022

D;.;.;.

Polyphen

1.0

D;.;D;D

Vest4

0.57

MutPred

0.49

Loss of methylation at K1530 (P = 0.012);.;Loss of methylation at K1530 (P = 0.012);Loss of methylation at K1530 (P = 0.012);

MVP

0.69

MPC

2.2

ClinPred

0.92

GERP RS

1.7

Varity_R

0.60

gMVP

0.76

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