rs4533485

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-196243189-C-A
• chr2-196243189-C-G
• chr2-196243189-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001348768.2(HECW2):​c.3530-985G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.0 (0 hom., cov: 23)
  • Failed GnomAD Quality Control
• Consequence: HECW2 NM_001348768.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.932
• Publications: 0 publications found

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: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
• neurodevelopmental disorder with hypotonia, seizures, and absent language

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Illumina

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348768.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HECW2	NM_001348768.2	MANE Select	c.3530-985G>T		intron	N/A	NP_001335697.1	Q9P2P5-1
	HECW2	NM_020760.4		c.3530-985G>T		intron	N/A	NP_065811.1	Q9P2P5-1
	HECW2	NM_001304840.3		c.2462-985G>T		intron	N/A	NP_001291769.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HECW2	ENST00000644978.2	MANE Select	c.3530-985G>T		intron	N/A	ENSP00000495418.1	Q9P2P5-1
	HECW2	ENST00000260983.8	TSL:1	c.3530-985G>T		intron	N/A	ENSP00000260983.2	Q9P2P5-1
	HECW2	ENST00000644030.1		c.3551-985G>T		intron	N/A	ENSP00000495504.1	A0A2R8Y6F3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 147140 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

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

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 147140 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 71306

African (AFR) AF: 0.00 AC: 0 AN: 39812

American (AMR) AF: 0.00 AC: 0 AN: 14894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 4974

South Asian (SAS) AF: 0.00 AC: 0 AN: 4690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67044

Other (OTH) AF: 0.00 AC: 0 AN: 2008

Alfa AF: 0.00 Hom.: 3947

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.6
DANN	Benign	0.86
PhyloP100		-0.93

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

Other links and lift over

dbSNP: rs4533485; hg19: chr2-197107913;