rs17310196

Variant names:

• chr2-196215918-G-A
• rs17310196
• NM_001348768.2:c.4554C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001348768.2(HECW2):​c.4554C>T​(p.Asn1518Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00777 in 1,613,780 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (57 hom.)
• Consequence: HECW2 NM_001348768.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.553
• Publications: 4 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-196215918-G-A is Benign according to our data. Variant chr2-196215918-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 708316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.553 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00518 (789/152276) while in subpopulation NFE AF = 0.00831 (565/68024). AF 95% confidence interval is 0.00774. There are 3 homozygotes in GnomAd4. There are 362 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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.4554C>T	p.Asn1518Asn	synonymous	Exon 28 of 29	NP_001335697.1	Q9P2P5-1
	HECW2	NM_020760.4		c.4554C>T	p.Asn1518Asn	synonymous	Exon 28 of 29	NP_065811.1	Q9P2P5-1
	HECW2	NM_001304840.3		c.3486C>T	p.Asn1162Asn	synonymous	Exon 26 of 27	NP_001291769.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HECW2	ENST00000644978.2	MANE Select	c.4554C>T	p.Asn1518Asn	synonymous	Exon 28 of 29	ENSP00000495418.1	Q9P2P5-1
	HECW2	ENST00000260983.8	TSL:1	c.4554C>T	p.Asn1518Asn	synonymous	Exon 28 of 29	ENSP00000260983.2	Q9P2P5-1
	HECW2	ENST00000644030.1		c.4575C>T	p.Asn1525Asn	synonymous	Exon 28 of 29	ENSP00000495504.1	A0A2R8Y6F3

Frequencies

GnomAD3 genomes AF: 0.00519 AC: 789 AN: 152158 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00933

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00830

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00580 AC: 1457 AN: 251402 AF XY: 0.00575

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00896

Gnomad NFE exome AF: 0.00861

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00804 AC: 11745 AN: 1461504 Hom.: 57 Cov.: 30 AF XY: 0.00799 AC XY: 5807 AN XY: 727076

African (AFR) AF: 0.00105 AC: 35 AN: 33468

American (AMR) AF: 0.00125 AC: 56 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 264 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00314 AC: 271 AN: 86248

European-Finnish (FIN) AF: 0.0100 AC: 536 AN: 53416

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5766

European-Non Finnish (NFE) AF: 0.00917 AC: 10194 AN: 1111678

Other (OTH) AF: 0.00621 AC: 375 AN: 60374

GnomAD4 genome AF: 0.00518 AC: 789 AN: 152276 Hom.: 3 Cov.: 32 AF XY: 0.00486 AC XY: 362 AN XY: 74462

African (AFR) AF: 0.00149 AC: 62 AN: 41548

American (AMR) AF: 0.00196 AC: 30 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4822

European-Finnish (FIN) AF: 0.00933 AC: 99 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00831 AC: 565 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00726 Hom.: 5

Bravo AF: 0.00476

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00807

EpiControl AF: 0.00782

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	HECW2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.8
DANN	Benign	0.81
PhyloP100		-0.55
Mutation Taster		=99/1	polymorphism

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: rs17310196; hg19: chr2-197080642; COSMIC: COSV53675305;