Genetic Variant NM_001348768.2:c.-35-50G>C (chr2-196433508-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001348768.2(HECW2):c.-35-50G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HECW2
NM_001348768.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.00

Publications

7 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:

LOC105373822 (HGNC:):

LOC105373822 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HECW2	NM_001348768.2 link	c.-35-50G>C		intron_variant	Intron 1 of 28	ENST00000644978.2	NP_001335697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HECW2	ENST00000644978.2 link	c.-35-50G>C		intron_variant	Intron 1 of 28		NM_001348768.2	ENSP00000495418.1		Q9P2P5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1220826

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

603006

African (AFR)

AF:

0.00

AC:

AN:

27382

American (AMR)

AF:

0.00

AC:

AN:

26762

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19348

East Asian (EAS)

AF:

0.00

AC:

AN:

36764

South Asian (SAS)

AF:

0.00

AC:

AN:

65386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3480

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

941700

Other (OTH)

AF:

0.00

AC:

AN:

51438

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

89835

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.40

(source)

DANN

Benign

0.59

PhyloP100

-2.0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over