NM_001348768.2:c.-35-50G>A

Variant names:

• chr2-196433508-C-T
• rs2204640
• NM_001348768.2:c.-35-50G>A

Variant summary

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

The NM_001348768.2(HECW2):​c.-35-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.971 in 1,372,716 control chromosomes in the GnomAD database, including 647,213 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 0.97 (71144 hom., cov: 32)
  • Exomes 𝑓: 0.97 (576069 hom.)
• Consequence: HECW2 NM_001348768.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00
• Publications: 7 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HECW2	NM_001348768.2	c.-35-50G>A		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.-35-50G>A		intron_variant	Intron 1 of 28		NM_001348768.2	ENSP00000495418.1

Frequencies

GnomAD3 genomes AF: 0.967 AC: 147076 AN: 152132 Hom.: 71095 Cov.: 32

Gnomad AFR AF: 0.953

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.973

Gnomad ASJ AF: 0.963

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.963

Gnomad FIN AF: 0.974

Gnomad MID AF: 0.920

Gnomad NFE AF: 0.970

Gnomad OTH AF: 0.964

GnomAD4 exome AF: 0.972 AC: 1185686 AN: 1220466 Hom.: 576069 Cov.: 16 AF XY: 0.971 AC XY: 585402 AN XY: 602846

African (AFR) AF: 0.951 AC: 26035 AN: 27372

American (AMR) AF: 0.980 AC: 26235 AN: 26758

Ashkenazi Jewish (ASJ) AF: 0.960 AC: 18572 AN: 19346

East Asian (EAS) AF: 1.00 AC: 36757 AN: 36764

South Asian (SAS) AF: 0.962 AC: 62904 AN: 65374

European-Finnish (FIN) AF: 0.979 AC: 47555 AN: 48564

Middle Eastern (MID) AF: 0.947 AC: 3290 AN: 3474

European-Non Finnish (NFE) AF: 0.971 AC: 914461 AN: 941392

Other (OTH) AF: 0.970 AC: 49877 AN: 51422

GnomAD4 genome AF: 0.967 AC: 147184 AN: 152250 Hom.: 71144 Cov.: 32 AF XY: 0.967 AC XY: 71973 AN XY: 74448

African (AFR) AF: 0.953 AC: 39572 AN: 41526

American (AMR) AF: 0.973 AC: 14898 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.963 AC: 3343 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5183 AN: 5188

South Asian (SAS) AF: 0.963 AC: 4647 AN: 4828

European-Finnish (FIN) AF: 0.974 AC: 10322 AN: 10594

Middle Eastern (MID) AF: 0.914 AC: 267 AN: 292

European-Non Finnish (NFE) AF: 0.970 AC: 66001 AN: 68018

Other (OTH) AF: 0.964 AC: 2040 AN: 2116

Alfa AF: 0.968 Hom.: 89835

Bravo AF: 0.966

Asia WGS AF: 0.980 AC: 3408 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.47
DANN	Benign	0.65
PhyloP100		-2.0
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: rs2204640; hg19: chr2-197298232;