2-196306451-C-T

Variant names:

• chr2-196306451-C-T
• rs4241189
• NM_001348768.2:c.2814+37G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001348768.2(HECW2):​c.2814+37G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.748 in 1,567,756 control chromosomes in the GnomAD database, including 441,951 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38882 hom., cov: 31)
  • Exomes 𝑓: 0.75 (403069 hom.)
• Consequence: HECW2 NM_001348768.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.721
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 2-196306451-C-T is Benign according to our data. Variant chr2-196306451-C-T is described in ClinVar as Benign. ClinVar VariationId is 1285333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.945 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HECW2	NM_001348768.2	c.2814+37G>A		intron_variant	Intron 13 of 28	ENST00000644978.2	NP_001335697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HECW2	ENST00000644978.2	c.2814+37G>A		intron_variant	Intron 13 of 28		NM_001348768.2	ENSP00000495418.1

Frequencies

GnomAD3 genomes AF: 0.707 AC: 107269 AN: 151730 Hom.: 38865 Cov.: 31

Gnomad AFR AF: 0.544

Gnomad AMI AF: 0.824

Gnomad AMR AF: 0.790

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.968

Gnomad SAS AF: 0.754

Gnomad FIN AF: 0.776

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.749

Gnomad OTH AF: 0.729

GnomAD2 exomes AF: 0.766 AC: 171977 AN: 224648 AF XY: 0.764

Gnomad AFR exome AF: 0.530

Gnomad AMR exome AF: 0.846

Gnomad ASJ exome AF: 0.763

Gnomad EAS exome AF: 0.978

Gnomad FIN exome AF: 0.782

Gnomad NFE exome AF: 0.745

Gnomad OTH exome AF: 0.748

GnomAD4 exome AF: 0.752 AC: 1065335 AN: 1415908 Hom.: 403069 Cov.: 25 AF XY: 0.753 AC XY: 528890 AN XY: 702416

African (AFR) AF: 0.526 AC: 16694 AN: 31724

American (AMR) AF: 0.837 AC: 32989 AN: 39432

Ashkenazi Jewish (ASJ) AF: 0.761 AC: 18700 AN: 24576

East Asian (EAS) AF: 0.954 AC: 36364 AN: 38132

South Asian (SAS) AF: 0.748 AC: 60265 AN: 80528

European-Finnish (FIN) AF: 0.775 AC: 40705 AN: 52522

Middle Eastern (MID) AF: 0.695 AC: 3876 AN: 5576

European-Non Finnish (NFE) AF: 0.748 AC: 811700 AN: 1084966

Other (OTH) AF: 0.753 AC: 44042 AN: 58452

GnomAD4 genome AF: 0.707 AC: 107338 AN: 151848 Hom.: 38882 Cov.: 31 AF XY: 0.711 AC XY: 52790 AN XY: 74236

African (AFR) AF: 0.544 AC: 22508 AN: 41402

American (AMR) AF: 0.790 AC: 12060 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 2666 AN: 3470

East Asian (EAS) AF: 0.967 AC: 4994 AN: 5162

South Asian (SAS) AF: 0.754 AC: 3623 AN: 4808

European-Finnish (FIN) AF: 0.776 AC: 8167 AN: 10524

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.749 AC: 50842 AN: 67910

Other (OTH) AF: 0.729 AC: 1534 AN: 2104

Alfa AF: 0.722 Hom.: 7946

Bravo AF: 0.702

Asia WGS AF: 0.833 AC: 2893 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with hypotonia, seizures, and absent language Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.049
DANN	Benign	0.67
PhyloP100		-0.72
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: rs4241189; hg19: chr2-197171175;