rs1057520120

Variant names:

• chr2-196325021-T-C
• rs1057520120
• NM_001348768.2:c.700A>G
• HECW2 p.Thr234Ala

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001304840.3(HECW2):​c.-268A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,605,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HECW2 NM_001304840.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81
• Publications: 1 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: Illumina, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11262339).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001304840.3. 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.700A>G	p.Thr234Ala	missense	Exon 6 of 29	NP_001335697.1	Q9P2P5-1
	HECW2	NM_001304840.3		c.-268A>G		5_prime_UTR_premature_start_codon_gain	Exon 5 of 27	NP_001291769.1
	HECW2	NM_020760.4		c.700A>G	p.Thr234Ala	missense	Exon 6 of 29	NP_065811.1	Q9P2P5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HECW2	ENST00000644978.2	MANE Select	c.700A>G	p.Thr234Ala	missense	Exon 6 of 29	ENSP00000495418.1	Q9P2P5-1
	HECW2	ENST00000260983.8	TSL:1	c.700A>G	p.Thr234Ala	missense	Exon 6 of 29	ENSP00000260983.2	Q9P2P5-1
	HECW2	ENST00000644030.1		c.700A>G	p.Thr234Ala	missense	Exon 6 of 29	ENSP00000495504.1	A0A2R8Y6F3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243534 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453516 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723262

African (AFR) AF: 0.00 AC: 0 AN: 32780

American (AMR) AF: 0.00 AC: 0 AN: 42652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25680

East Asian (EAS) AF: 0.00 AC: 0 AN: 39494

South Asian (SAS) AF: 0.00 AC: 0 AN: 85038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5174

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109506

Other (OTH) AF: 0.00 AC: 0 AN: 59920

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Benign	0.84
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.13
Sift	Benign	0.22	T
Sift4G	Benign	0.71	T
Varity_R		0.13
gMVP		0.40
Mutation Taster		=90/10	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

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

Other links and lift over

dbSNP: rs1057520120;

hg19: chr2-197189745;

COSMIC: COSV53651678;