2-196306451-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

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

HECW2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348768.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HECW2	NM_001348768.2	MANE Select	c.2814+37G>A	intron	N/A	NP_001335697.1	Q9P2P5-1
HECW2	NM_020760.4		c.2814+37G>A	intron	N/A	NP_065811.1	Q9P2P5-1
HECW2	NM_001304840.3		c.1746+37G>A	intron	N/A	NP_001291769.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HECW2	ENST00000644978.2	MANE Select	c.2814+37G>A	intron	N/A	ENSP00000495418.1	Q9P2P5-1
HECW2	ENST00000260983.8	TSL:1	c.2814+37G>A	intron	N/A	ENSP00000260983.2	Q9P2P5-1
HECW2	ENST00000644030.1		c.2835+37G>A	intron	N/A	ENSP00000495504.1	A0A2R8Y6F3

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

GnomAD2 exomes

AF:

0.766

AC:

171977

AN:

224648

AF XY:

0.764

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 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

African (AFR)

AF:

0.526

AC:

16694

AN:

31724

American (AMR)

AF:

0.837

AC:

32989

AN:

39432

Ashkenazi Jewish (ASJ)

AF:

0.761

AC:

18700

AN:

24576

East Asian (EAS)

AF:

0.954

AC:

36364

AN:

38132

South Asian (SAS)

AF:

0.748

AC:

60265

AN:

80528

European-Finnish (FIN)

AF:

0.775

AC:

40705

AN:

52522

Middle Eastern (MID)

AF:

0.695

AC:

3876

AN:

5576

European-Non Finnish (NFE)

AF:

0.748

AC:

811700

AN:

1084966

Other (OTH)

AF:

0.753

AC:

44042

AN:

58452

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

10724

21447

32171

42894

53618

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19978

39956

59934

79912

99890

<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:

0.707

AC:

107338

AN:

151848

Hom.:

38882

Cov.:

AF XY:

0.711

AC XY:

52790

AN XY:

74236

show subpopulations

African (AFR)

AF:

0.544

AC:

22508

AN:

41402

American (AMR)

AF:

0.790

AC:

12060

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.768

AC:

2666

AN:

3470

East Asian (EAS)

AF:

0.967

AC:

4994

AN:

5162

South Asian (SAS)

AF:

0.754

AC:

3623

AN:

4808

European-Finnish (FIN)

AF:

0.776

AC:

8167

AN:

10524

Middle Eastern (MID)

AF:

0.667

AC:

196

AN:

294

European-Non Finnish (NFE)

AF:

0.749

AC:

50842

AN:

67910

Other (OTH)

AF:

0.729

AC:

1534

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1510

3020

4530

6040

7550

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

818

1636

2454

3272

4090

<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:

0.722

Hom.:

7946

Bravo

AF:

0.702

Asia WGS

AF:

0.833

AC:

2893

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodevelopmental disorder with hypotonia, seizures, and absent language (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.049

(source)

DANN

Benign

0.67

PhyloP100

-0.72

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over