Genetic Variant HECW2:p.Thr914Lys (chr2-196306561-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001348768.2(HECW2):c.2741C>A(p.Thr914Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,584 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T914M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HECW2
NM_001348768.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.28

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HECW2	NM_001348768.2 link	c.2741C>A	p.Thr914Lys	missense_variant	Exon 13 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.2741C>A	p.Thr914Lys	missense_variant	Exon 13 of 29		NM_001348768.2	ENSP00000495418.1		Q9P2P5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460584

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726612

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33382

American (AMR)

AF:

0.00

AC:

AN:

44574

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39572

South Asian (SAS)

AF:

0.00

AC:

AN:

86066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111382

Other (OTH)

AF:

0.00

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;.;T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

.;D;.;D

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.50

D;D;D;D

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

1.8

L;.;L;L

PhyloP100

6.3

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.6

D;.;.;.

REVEL

Uncertain

0.49

Sift

Uncertain

0.0070

D;.;.;.

Sift4G

Uncertain

0.031

D;.;.;.

Polyphen

0.55

P;.;P;P

Vest4

0.54

MutPred

0.40

Gain of ubiquitination at T914 (P = 0.0325);.;Gain of ubiquitination at T914 (P = 0.0325);Gain of ubiquitination at T914 (P = 0.0325);

MVP

0.87

MPC

0.41

ClinPred

0.87

GERP RS

5.7

Varity_R

0.20

gMVP

0.78

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over