2-196242161-CC-TT

Variant names:

• chr2-196242161-CC-TT
• NM_001348768.2:c.3572_3573delGGinsAA
• HECW2 p.Arg1191Gln

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS1_Very_Strong PM1 PM5 PP3

The NM_001348768.2(HECW2):​c.3572_3573delGGinsAA​(p.Arg1191Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1191W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HECW2 NM_001348768.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• 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):

• neurodevelopmental disorder with hypotonia, seizures, and absent language

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina
• complex neurodevelopmental disorder

  Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS1: Transcript NM_001348768.2 (HECW2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001348768.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-196242163-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 809132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.3572_3573delGGinsAA	p.Arg1191Gln	missense	N/A	NP_001335697.1	Q9P2P5-1
	HECW2	NM_020760.4		c.3572_3573delGGinsAA	p.Arg1191Gln	missense	N/A	NP_065811.1	Q9P2P5-1
	HECW2	NM_001304840.3		c.2504_2505delGGinsAA	p.Arg835Gln	missense	N/A	NP_001291769.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HECW2	ENST00000644978.2	MANE Select	c.3572_3573delGGinsAA	p.Arg1191Gln	missense	N/A	ENSP00000495418.1	Q9P2P5-1
	HECW2	ENST00000260983.8	TSL:1	c.3572_3573delGGinsAA	p.Arg1191Gln	missense	N/A	ENSP00000260983.2	Q9P2P5-1
	HECW2	ENST00000644030.1		c.3593_3594delGGinsAA	p.Arg1198Gln	missense	N/A	ENSP00000495504.1	A0A2R8Y6F3

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-197106885;