rs2204641

Variant names:

• chr2-196433498-T-C
• rs2204641
• NM_001348768.2:c.-35-40A>G

Variant summary

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

The NM_001348768.2(HECW2):​c.-35-40A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.967 in 1,443,452 control chromosomes in the GnomAD database, including 674,708 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 0.95 (68450 hom., cov: 32)
  • Exomes 𝑓: 0.97 (606258 hom.)
• Consequence: HECW2 NM_001348768.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.60
• Publications: 5 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

LOC105373822 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HECW2	NM_001348768.2	c.-35-40A>G		intron_variant	Intron 1 of 28	ENST00000644978.2	NP_001335697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HECW2	ENST00000644978.2	c.-35-40A>G		intron_variant	Intron 1 of 28		NM_001348768.2	ENSP00000495418.1

Frequencies

GnomAD3 genomes AF: 0.948 AC: 144155 AN: 152110 Hom.: 68412 Cov.: 32

Gnomad AFR AF: 0.889

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.966

Gnomad ASJ AF: 0.959

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.952

Gnomad FIN AF: 0.974

Gnomad MID AF: 0.898

Gnomad NFE AF: 0.970

Gnomad OTH AF: 0.948

GnomAD4 exome AF: 0.969 AC: 1250987 AN: 1291224 Hom.: 606258 Cov.: 18 AF XY: 0.968 AC XY: 617664 AN XY: 637940

African (AFR) AF: 0.891 AC: 25858 AN: 29032

American (AMR) AF: 0.977 AC: 30856 AN: 31588

Ashkenazi Jewish (ASJ) AF: 0.956 AC: 19612 AN: 20510

East Asian (EAS) AF: 0.998 AC: 37909 AN: 37966

South Asian (SAS) AF: 0.951 AC: 66403 AN: 69794

European-Finnish (FIN) AF: 0.979 AC: 48908 AN: 49950

Middle Eastern (MID) AF: 0.930 AC: 3450 AN: 3710

European-Non Finnish (NFE) AF: 0.971 AC: 966027 AN: 994714

Other (OTH) AF: 0.963 AC: 51964 AN: 53960

GnomAD4 genome AF: 0.948 AC: 144248 AN: 152228 Hom.: 68450 Cov.: 32 AF XY: 0.947 AC XY: 70528 AN XY: 74438

African (AFR) AF: 0.889 AC: 36912 AN: 41512

American (AMR) AF: 0.966 AC: 14782 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.959 AC: 3327 AN: 3470

East Asian (EAS) AF: 0.996 AC: 5163 AN: 5186

South Asian (SAS) AF: 0.951 AC: 4593 AN: 4828

European-Finnish (FIN) AF: 0.974 AC: 10324 AN: 10596

Middle Eastern (MID) AF: 0.890 AC: 260 AN: 292

European-Non Finnish (NFE) AF: 0.970 AC: 65971 AN: 68018

Other (OTH) AF: 0.948 AC: 2005 AN: 2114

Alfa AF: 0.960 Hom.: 90243

Bravo AF: 0.944

Asia WGS AF: 0.962 AC: 3348 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0050
DANN	Benign	0.50
PhyloP100		-2.6
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: rs2204641; hg19: chr2-197298222;