2-196196428-C-T

Variant names:

• chr2-196196428-C-T
• rs4850679
• NM_001348768.2:c.*4849G>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.*4849G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 152,088 control chromosomes in the GnomAD database, including 33,180 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 0.64 (33175 hom., cov: 32)
  • Exomes 𝑓: 0.92 (5 hom.)
• Consequence: HECW2 NM_001348768.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.274
• Publications: 3 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.81 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.*4849G>A		3_prime_UTR	Exon 29 of 29	NP_001335697.1	Q9P2P5-1
	HECW2	NM_020760.4		c.*4849G>A		3_prime_UTR	Exon 29 of 29	NP_065811.1	Q9P2P5-1
	HECW2	NM_001304840.3		c.*4849G>A		3_prime_UTR	Exon 27 of 27	NP_001291769.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HECW2	ENST00000644978.2	MANE Select	c.*4849G>A		3_prime_UTR	Exon 29 of 29	ENSP00000495418.1	Q9P2P5-1
	HECW2	ENST00000260983.8	TSL:1	c.*4849G>A		3_prime_UTR	Exon 29 of 29	ENSP00000260983.2	Q9P2P5-1
	HECW2	ENST00000867916.1		c.*4849G>A		3_prime_UTR	Exon 29 of 29	ENSP00000537975.1

Frequencies

GnomAD3 genomes AF: 0.641 AC: 97464 AN: 151958 Hom.: 33159 Cov.: 32

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.722

Gnomad AMR AF: 0.711

Gnomad ASJ AF: 0.691

Gnomad EAS AF: 0.831

Gnomad SAS AF: 0.742

Gnomad FIN AF: 0.765

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.729

Gnomad OTH AF: 0.650

GnomAD4 exome AF: 0.917 AC: 11 AN: 12 Hom.: 5 Cov.: 0 AF XY: 1.00 AC XY: 8 AN XY: 8

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 0.900 AC: 9 AN: 10

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.641 AC: 97514 AN: 152076 Hom.: 33175 Cov.: 32 AF XY: 0.646 AC XY: 48012 AN XY: 74342

African (AFR) AF: 0.399 AC: 16546 AN: 41464

American (AMR) AF: 0.712 AC: 10870 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.691 AC: 2395 AN: 3468

East Asian (EAS) AF: 0.831 AC: 4302 AN: 5180

South Asian (SAS) AF: 0.742 AC: 3581 AN: 4828

European-Finnish (FIN) AF: 0.765 AC: 8081 AN: 10568

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.729 AC: 49529 AN: 67984

Other (OTH) AF: 0.646 AC: 1361 AN: 2108

Alfa AF: 0.702 Hom.: 20717

Bravo AF: 0.625

Asia WGS AF: 0.730 AC: 2539 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.2
DANN	Benign	0.23
PhyloP100		0.27
Mutation Taster		=99/1	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: rs4850679; hg19: chr2-197061152;