2-196243189-C-T

Variant names:

• chr2-196243189-C-T
• rs4533485
• NM_001348768.2:c.3530-985G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001348768.2(HECW2):​c.3530-985G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.837 in 146,868 control chromosomes in the GnomAD database, including 52,557 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 0.84 (52557 hom., cov: 23)
• Consequence: HECW2 NM_001348768.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.932

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HECW2	NM_001348768.2	c.3530-985G>A		intron_variant	Intron 19 of 28	ENST00000644978.2	NP_001335697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HECW2	ENST00000644978.2	c.3530-985G>A		intron_variant	Intron 19 of 28		NM_001348768.2	ENSP00000495418.1

Frequencies

GnomAD3 genomes AF: 0.837 AC: 122892 AN: 146802 Hom.: 52534 Cov.: 23

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.859

Gnomad AMR AF: 0.859

Gnomad ASJ AF: 0.915

Gnomad EAS AF: 0.819

Gnomad SAS AF: 0.867

Gnomad FIN AF: 0.946

Gnomad MID AF: 0.836

Gnomad NFE AF: 0.926

Gnomad OTH AF: 0.845

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.837 AC: 122952 AN: 146868 Hom.: 52557 Cov.: 23 AF XY: 0.837 AC XY: 59580 AN XY: 71186

Gnomad4 AFR AF: 0.645

Gnomad4 AMR AF: 0.860

Gnomad4 ASJ AF: 0.915

Gnomad4 EAS AF: 0.819

Gnomad4 SAS AF: 0.867

Gnomad4 FIN AF: 0.946

Gnomad4 NFE AF: 0.926

Gnomad4 OTH AF: 0.843

Alfa AF: 0.848 Hom.: 3947

Bravo AF: 0.820

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.6
DANN	Benign	0.92

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

Other links and lift over

dbSNP: rs4533485; hg19: chr2-197107913;