chr2-196201240-C-A

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.*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

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0260

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):

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

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=-0.84).

BP6

Variant 2-196201240-C-A is Benign according to our data. Variant chr2-196201240-C-A is described in ClinVar as Benign. ClinVar VariationId is 1285331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.811 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.*37G>T	3_prime_UTR	Exon 29 of 29	NP_001335697.1	Q9P2P5-1
HECW2	NM_020760.4		c.*37G>T	3_prime_UTR	Exon 29 of 29	NP_065811.1	Q9P2P5-1
HECW2	NM_001304840.3		c.*37G>T	3_prime_UTR	Exon 27 of 27	NP_001291769.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HECW2	ENST00000644978.2	MANE Select	c.*37G>T	3_prime_UTR	Exon 29 of 29	ENSP00000495418.1	Q9P2P5-1
HECW2	ENST00000260983.8	TSL:1	c.*37G>T	3_prime_UTR	Exon 29 of 29	ENSP00000260983.2	Q9P2P5-1
HECW2	ENST00000644030.1		c.*37G>T	3_prime_UTR	Exon 29 of 29	ENSP00000495504.1	A0A2R8Y6F3

Frequencies

GnomAD3 genomes

AF:

0.677

AC:

102883

AN:

151936

Hom.:

35218

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.721

AC:

180561

AN:

250384

AF XY:

0.723

show subpopulations

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 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.:

AF XY:

0.717

AC XY:

429906

AN XY:

599328

show subpopulations

African (AFR)

AF:

0.561

AC:

15529

AN:

27686

American (AMR)

AF:

0.752

AC:

33272

AN:

44252

Ashkenazi Jewish (ASJ)

AF:

0.687

AC:

16695

AN:

24288

East Asian (EAS)

AF:

0.855

AC:

32774

AN:

38344

South Asian (SAS)

AF:

0.753

AC:

60544

AN:

80366

European-Finnish (FIN)

AF:

0.725

AC:

38591

AN:

53222

Middle Eastern (MID)

AF:

0.649

AC:

3422

AN:

5276

European-Non Finnish (NFE)

AF:

0.711

AC:

606335

AN:

853212

Other (OTH)

AF:

0.717

AC:

36616

AN:

51094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

11687

23374

35062

46749

58436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13556

27112

40668

54224

67780

<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:

0.677

AC:

102951

AN:

152054

Hom.:

35244

Cov.:

AF XY:

0.679

AC XY:

50495

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.568

AC:

23524

AN:

41446

American (AMR)

AF:

0.715

AC:

10929

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.684

AC:

2374

AN:

3470

East Asian (EAS)

AF:

0.832

AC:

4311

AN:

5182

South Asian (SAS)

AF:

0.748

AC:

3605

AN:

4822

European-Finnish (FIN)

AF:

0.733

AC:

7749

AN:

10576

Middle Eastern (MID)

AF:

0.660

AC:

194

AN:

294

European-Non Finnish (NFE)

AF:

0.709

AC:

48185

AN:

67964

Other (OTH)

AF:

0.684

AC:

1447

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1715

3431

5146

6862

8577

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

826

1652

2478

3304

4130

<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:

0.686

Hom.:

55064

Bravo

AF:

0.672

Asia WGS

AF:

0.755

AC:

2627

AN:

3478

ClinVar

ClinVar submissions as Germline

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

-0.84

CADD

Benign

0.90

(source)

DANN

Benign

0.54

PhyloP100

0.026

Mutation Taster

=97/3

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