rs1553496847

Positions:

• chr2-196307935-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_001348768.2(HECW2):​c.2585G>A​(p.Arg862Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HECW2 NM_001348768.2 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.56

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HECW2. . Gene score misZ 3.3052 (greater than the threshold 3.09). Trascript score misZ 3.6429 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with hypotonia, seizures, and absent language, complex neurodevelopmental disorder.
• PP5: Variant 2-196307935-C-T is Pathogenic according to our data. Variant chr2-196307935-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521619.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HECW2	NM_001348768.2	c.2585G>A	p.Arg862Gln	missense_variant, splice_region_variant	11/29	ENST00000644978.2	NP_001335697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HECW2	ENST00000644978.2	c.2585G>A	p.Arg862Gln	missense_variant, splice_region_variant	11/29		NM_001348768.2	ENSP00000495418.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1378124 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 679290

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 14, 2020

Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	36
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T;.;T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.7	M;.;M;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.6	D;.;.;.
REVEL	Pathogenic	0.72
Sift	Benign	0.032	D;.;.;.
Sift4G	Benign	0.076	T;.;.;.
Polyphen		1.0	D;.;D;D
Vest4		0.52
MutPred		0.29		Loss of stability (P = 0.0641);.;Loss of stability (P = 0.0641);Loss of stability (P = 0.0641);
MVP		0.81
MPC		0.43
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.49
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.38		Position offset: 50
DS_DL_spliceai		0.41		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553496847; hg19: chr2-197172659;