2-196217017-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_001348768.2(HECW2):c.4485G>T(p.Arg1495Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,371,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1495K) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: HECW2 NM_001348768.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.495

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-196217018-C-T is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, HECW2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 2-196217017-C-A is Pathogenic according to our data. Variant chr2-196217017-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521150.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-196217017-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HECW2	NM_001348768.2	c.4485G>T	p.Arg1495Ser	missense_variant	27/29	ENST00000644978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HECW2	ENST00000644978.2	c.4485G>T	p.Arg1495Ser	missense_variant	27/29		NM_001348768.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1371480 Hom.: 0 Cov.: 28 AF XY: 0.00000147 AC XY: 1 AN XY: 680156

Gnomad4 AFR exome AF: 0.0000362

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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.7	M;.;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.8	D;.;.;.
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0010	D;.;.;.
Polyphen		0.99	D;.;D;D
Vest4		0.87
MutPred		0.81		Loss of MoRF binding (P = 0.0704);.;Loss of MoRF binding (P = 0.0704);Loss of MoRF binding (P = 0.0704);
MVP		0.94
MPC		2.3
ClinPred		0.98	D
GERP RS		3.5
Varity_R		0.87
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs774316240; hg19: chr2-197081741;