Genetic Variant NM_001348768.2:c.-35-40A>G (chr2-196433498-T-C) – 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.-35-40A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.967 in 1,443,452 control chromosomes in the GnomAD database, including 674,708 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 0.95 ( 68450 hom., cov: 32)

Exomes 𝑓: 0.97 ( 606258 hom. )

Consequence

HECW2
NM_001348768.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.60

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HECW2	NM_001348768.2 link	c.-35-40A>G		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.-35-40A>G		intron_variant	Intron 1 of 28		NM_001348768.2	ENSP00000495418.1		Q9P2P5-1

Frequencies

GnomAD3 genomes

AF:

0.948

AC:

144155

AN:

152110

Hom.:

68412

Cov.:

show subpopulations

Gnomad AFR

AF:

0.889

Gnomad AMI

AF:

0.999

Gnomad AMR

AF:

0.966

Gnomad ASJ

AF:

0.959

Gnomad EAS

AF:

0.996

Gnomad SAS

AF:

0.952

Gnomad FIN

AF:

0.974

Gnomad MID

AF:

0.898

Gnomad NFE

AF:

0.970

Gnomad OTH

AF:

0.948

GnomAD4 exome

AF:

0.969

AC:

1250987

AN:

1291224

Hom.:

606258

Cov.:

AF XY:

0.968

AC XY:

617664

AN XY:

637940

show subpopulations

Gnomad4 AFR exome

AF:

0.891

Gnomad4 AMR exome

AF:

0.977

Gnomad4 ASJ exome

AF:

0.956

Gnomad4 EAS exome

AF:

0.998

Gnomad4 SAS exome

AF:

0.951

Gnomad4 FIN exome

AF:

0.979

Gnomad4 NFE exome

AF:

0.971

Gnomad4 OTH exome

AF:

0.963

GnomAD4 genome

AF:

0.948

AC:

144248

AN:

152228

Hom.:

68450

Cov.:

AF XY:

0.947

AC XY:

70528

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.889

Gnomad4 AMR

AF:

0.966

Gnomad4 ASJ

AF:

0.959

Gnomad4 EAS

AF:

0.996

Gnomad4 SAS

AF:

0.951

Gnomad4 FIN

AF:

0.974

Gnomad4 NFE

AF:

0.970

Gnomad4 OTH

AF:

0.948

Alfa

AF:

0.962

Hom.:

69512

Bravo

AF:

0.944

Asia WGS

AF:

0.962

AC:

3348

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.0050

DANN

Benign

0.50

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