2-196215918-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001348768.2(HECW2):c.4554C>T(p.Asn1518Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00777 in 1,613,780 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0080 ( 57 hom. )

Consequence

HECW2
NM_001348768.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.553

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD, AR Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
neurodevelopmental disorder with hypotonia, seizures, and absent language
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P

HECW2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 2-196215918-G-A is Benign according to our data. Variant chr2-196215918-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 708316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-196215918-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 708316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-196215918-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 708316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-196215918-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 708316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-196215918-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 708316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-196215918-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 708316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-196215918-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 708316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-196215918-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 708316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-196215918-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 708316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-196215918-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 708316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-196215918-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 708316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-196215918-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 708316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.553 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00518 (789/152276) while in subpopulation NFE AF = 0.00831 (565/68024). AF 95% confidence interval is 0.00774. There are 3 homozygotes in GnomAd4. There are 362 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HECW2	NM_001348768.2 link	c.4554C>T	p.Asn1518Asn	synonymous_variant	Exon 28 of 29	ENST00000644978.2	NP_001335697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HECW2	ENST00000644978.2 link	c.4554C>T	p.Asn1518Asn	synonymous_variant	Exon 28 of 29		NM_001348768.2	ENSP00000495418.1		Q9P2P5-1

Frequencies

GnomAD3 genomes

AF:

0.00519

AC:

789

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00933

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00830

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00580

AC:

1457

AN:

251402

AF XY:

0.00575

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.0108

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00896

Gnomad NFE exome

AF:

0.00861

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00804

AC:

11745

AN:

1461504

Hom.:

Cov.:

AF XY:

0.00799

AC XY:

5807

AN XY:

727076

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33468

American (AMR)

AF:

0.00125

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

264

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00314

AC:

271

AN:

86248

European-Finnish (FIN)

AF:

0.0100

AC:

536

AN:

53416

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00917

AC:

10194

AN:

1111678

Other (OTH)

AF:

0.00621

AC:

375

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

544

1088

1632

2176

2720

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

390

780

1170

1560

1950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00518

AC:

789

AN:

152276

Hom.:

Cov.:

AF XY:

0.00486

AC XY:

362

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

41548

American (AMR)

AF:

0.00196

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00166

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00933

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00831

AC:

565

AN:

68024

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

121

161

201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00726

Hom.:

Bravo

AF:

0.00476

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00807

EpiControl

AF:

0.00782

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 27, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HECW2: BP4, BP7, BS2 -

HECW2-related disorder

Benign:1

Apr 26, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

3.8

(source)

DANN

Benign

0.81

PhyloP100

-0.55

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over