rs4850695

Variant names:

• chr2-196288535-G-A
• rs4850695
• NM_001348768.2:c.3000+4030C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-196288535-G-A
• chr2-196288535-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020760.4(HECW2):​c.3000+4030C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.633 in 152,060 control chromosomes in the GnomAD database, including 34,521 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 0.63 (34516 hom., cov: 31)
  • Exomes 𝑓: 0.92 (5 hom.)
• Consequence: HECW2 NM_020760.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.985
• 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: AD, AR Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
• neurodevelopmental disorder with hypotonia, seizures, and absent language

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020760.4. 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.3000+4030C>T		intron	N/A	NP_001335697.1
	HECW2	NM_020760.4		c.3000+4030C>T		intron	N/A	NP_065811.1
	HECW2	NM_001304840.3		c.1932+4030C>T		intron	N/A	NP_001291769.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HECW2	ENST00000644978.2	MANE Select	c.3000+4030C>T		intron	N/A	ENSP00000495418.1
	HECW2	ENST00000260983.8	TSL:1	c.3000+4030C>T		intron	N/A	ENSP00000260983.2
	HECW2	ENST00000644030.1		c.3021+4030C>T		intron	N/A	ENSP00000495504.1

Frequencies

GnomAD3 genomes AF: 0.633 AC: 96231 AN: 151930 Hom.: 34514 Cov.: 31

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.870

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.724

Gnomad EAS AF: 0.948

Gnomad SAS AF: 0.669

Gnomad FIN AF: 0.803

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.762

Gnomad OTH AF: 0.664

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) AC: 0 AN: 0

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

Other (OTH) AF: 1.00 AC: 2 AN: 2

GnomAD4 genome AF: 0.633 AC: 96246 AN: 152048 Hom.: 34516 Cov.: 31 AF XY: 0.639 AC XY: 47485 AN XY: 74344

African (AFR) AF: 0.274 AC: 11346 AN: 41428

American (AMR) AF: 0.759 AC: 11593 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.724 AC: 2515 AN: 3472

East Asian (EAS) AF: 0.948 AC: 4919 AN: 5188

South Asian (SAS) AF: 0.670 AC: 3228 AN: 4818

European-Finnish (FIN) AF: 0.803 AC: 8500 AN: 10584

Middle Eastern (MID) AF: 0.647 AC: 189 AN: 292

European-Non Finnish (NFE) AF: 0.762 AC: 51767 AN: 67980

Other (OTH) AF: 0.663 AC: 1396 AN: 2104

Alfa AF: 0.726 Hom.: 67782

Bravo AF: 0.617

Asia WGS AF: 0.774 AC: 2691 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.2
DANN	Benign	0.53
PhyloP100		0.98
Mutation Taster		=100/0	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: rs4850695; hg19: chr2-197153259;