Genetic Variant HECW2:c.-35-50G>A (chr2-196433508-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001348768.2(HECW2):c.-35-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.971 in 1,372,716 control chromosomes in the GnomAD database, including 647,213 homozygotes. 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: 𝑓 0.97 ( 71144 hom., cov: 32)

Exomes 𝑓: 0.97 ( 576069 hom. )

Consequence

HECW2
NM_001348768.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.00

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 links:

LOC105373822 (HGNC:):

LOC105373822 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.967

AC:

147076

AN:

152132

Hom.:

71095

Cov.:

show subpopulations

Gnomad AFR

AF:

0.953

Gnomad AMI

AF:

0.999

Gnomad AMR

AF:

0.973

Gnomad ASJ

AF:

0.963

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.963

Gnomad FIN

AF:

0.974

Gnomad MID

AF:

0.920

Gnomad NFE

AF:

0.970

Gnomad OTH

AF:

0.964

GnomAD4 exome

AF:

0.972

AC:

1185686

AN:

1220466

Hom.:

576069

Cov.:

AF XY:

0.971

AC XY:

585402

AN XY:

602846

show subpopulations

Gnomad4 AFR exome

AF:

0.951

Gnomad4 AMR exome

AF:

0.980

Gnomad4 ASJ exome

AF:

0.960

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.962

Gnomad4 FIN exome

AF:

0.979

Gnomad4 NFE exome

AF:

0.971

Gnomad4 OTH exome

AF:

0.970

GnomAD4 genome

AF:

0.967

AC:

147184

AN:

152250

Hom.:

71144

Cov.:

AF XY:

0.967

AC XY:

71973

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.953

Gnomad4 AMR

AF:

0.973

Gnomad4 ASJ

AF:

0.963

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.963

Gnomad4 FIN

AF:

0.974

Gnomad4 NFE

AF:

0.970

Gnomad4 OTH

AF:

0.964

Alfa

AF:

0.968

Hom.:

68499

Bravo

AF:

0.966

Asia WGS

AF:

0.980

AC:

3408

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.47

DANN

Benign

0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over