2-196394265-C-T

Variant names:

• chr2-196394265-C-T
• rs4850704
• NM_001348768.2:c.292+38867G>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.292+38867G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 151,970 control chromosomes in the GnomAD database, including 29,292 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 0.58 (29292 hom., cov: 31)
• Consequence: HECW2 NM_001348768.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31
• Publications: 2 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=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.818 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.292+38867G>A		intron	N/A	NP_001335697.1	Q9P2P5-1
	HECW2	NM_020760.4		c.292+38867G>A		intron	N/A	NP_065811.1	Q9P2P5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HECW2	ENST00000644978.2	MANE Select	c.292+38867G>A		intron	N/A	ENSP00000495418.1	Q9P2P5-1
	HECW2	ENST00000260983.8	TSL:1	c.292+38867G>A		intron	N/A	ENSP00000260983.2	Q9P2P5-1
	HECW2	ENST00000644030.1		c.292+38867G>A		intron	N/A	ENSP00000495504.1	A0A2R8Y6F3

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88766 AN: 151852 Hom.: 29289 Cov.: 31

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.721

Gnomad ASJ AF: 0.652

Gnomad EAS AF: 0.838

Gnomad SAS AF: 0.565

Gnomad FIN AF: 0.787

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.695

Gnomad OTH AF: 0.619

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

GnomAD4 genome AF: 0.584 AC: 88787 AN: 151970 Hom.: 29292 Cov.: 31 AF XY: 0.591 AC XY: 43909 AN XY: 74280

African (AFR) AF: 0.260 AC: 10748 AN: 41402

American (AMR) AF: 0.722 AC: 11021 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 2259 AN: 3466

East Asian (EAS) AF: 0.838 AC: 4343 AN: 5180

South Asian (SAS) AF: 0.565 AC: 2712 AN: 4802

European-Finnish (FIN) AF: 0.787 AC: 8326 AN: 10582

Middle Eastern (MID) AF: 0.466 AC: 136 AN: 292

European-Non Finnish (NFE) AF: 0.695 AC: 47215 AN: 67954

Other (OTH) AF: 0.619 AC: 1306 AN: 2110

Alfa AF: 0.640 Hom.: 4138

Bravo AF: 0.567

Asia WGS AF: 0.683 AC: 2377 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.53
DANN	Benign	0.72
PhyloP100		-1.3
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: rs4850704; hg19: chr2-197258989;