NM_001348768.2:c.3530-985G>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• 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: Benign. The variant received -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.

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>A		intron	N/A	NP_001335697.1	Q9P2P5-1
	HECW2	NM_020760.4		c.3530-985G>A		intron	N/A	NP_065811.1	Q9P2P5-1
	HECW2	NM_001304840.3		c.2462-985G>A		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>A		intron	N/A	ENSP00000495418.1	Q9P2P5-1
	HECW2	ENST00000260983.8	TSL:1	c.3530-985G>A		intron	N/A	ENSP00000260983.2	Q9P2P5-1
	HECW2	ENST00000644030.1		c.3551-985G>A		intron	N/A	ENSP00000495504.1	A0A2R8Y6F3

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

African (AFR) AF: 0.645 AC: 25599 AN: 39690

American (AMR) AF: 0.860 AC: 12798 AN: 14886

Ashkenazi Jewish (ASJ) AF: 0.915 AC: 3153 AN: 3446

East Asian (EAS) AF: 0.819 AC: 4059 AN: 4954

South Asian (SAS) AF: 0.867 AC: 4036 AN: 4654

European-Finnish (FIN) AF: 0.946 AC: 8552 AN: 9044

Middle Eastern (MID) AF: 0.848 AC: 234 AN: 276

European-Non Finnish (NFE) AF: 0.926 AC: 62033 AN: 66984

Other (OTH) AF: 0.843 AC: 1708 AN: 2026

Alfa AF: 0.848 Hom.: 3947

Bravo AF: 0.820

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.6
DANN	Benign	0.92
PhyloP100		-0.93
Mutation Taster		=100/0	polymorphism (auto)

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;