rs2204641

chr2-196433498-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

LOC105373822 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
HECW2	NM_001348768.2	c.-35-40A>G		intron_variant		ENST00000644978.2
LOC105373822	XR_923746.4	n.44-2286T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HECW2	ENST00000644978.2	c.-35-40A>G		intron_variant			NM_001348768.2	P1

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

Gnomad4 AFR exome AF: 0.891

Gnomad4 AMR exome AF: 0.977

Gnomad4 ASJ exome AF: 0.956

Gnomad4 EAS exome AF: 0.998

Gnomad4 SAS exome AF: 0.951

Gnomad4 FIN exome AF: 0.979

Gnomad4 NFE exome AF: 0.971

Gnomad4 OTH exome AF: 0.963

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

Gnomad4 AFR AF: 0.889

Gnomad4 AMR AF: 0.966

Gnomad4 ASJ AF: 0.959

Gnomad4 EAS AF: 0.996

Gnomad4 SAS AF: 0.951

Gnomad4 FIN AF: 0.974

Gnomad4 NFE AF: 0.970

Gnomad4 OTH AF: 0.948

Alfa AF: 0.962 Hom.: 69512

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2204641; hg19: chr2-197298222;