NM_001348768.2:c.*37G>C

Variant names:

• chr2-196201240-C-G
• rs3820908
• NM_001348768.2:c.*37G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001348768.2(HECW2):​c.*37G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000847 in 1,180,070 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: HECW2 NM_001348768.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0260
• 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):

• neurodevelopmental disorder with hypotonia, seizures, and absent language

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina
• complex neurodevelopmental disorder

  Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348768.2. 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.*37G>C		3_prime_UTR	Exon 29 of 29	NP_001335697.1	Q9P2P5-1
	HECW2	NM_020760.4		c.*37G>C		3_prime_UTR	Exon 29 of 29	NP_065811.1	Q9P2P5-1
	HECW2	NM_001304840.3		c.*37G>C		3_prime_UTR	Exon 27 of 27	NP_001291769.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HECW2	ENST00000644978.2	MANE Select	c.*37G>C		3_prime_UTR	Exon 29 of 29	ENSP00000495418.1	Q9P2P5-1
	HECW2	ENST00000260983.8	TSL:1	c.*37G>C		3_prime_UTR	Exon 29 of 29	ENSP00000260983.2	Q9P2P5-1
	HECW2	ENST00000644030.1		c.*37G>C		3_prime_UTR	Exon 29 of 29	ENSP00000495504.1	A0A2R8Y6F3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.47e-7 AC: 1 AN: 1180070 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 600392

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27740

American (AMR) AF: 0.00 AC: 0 AN: 44262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24314

East Asian (EAS) AF: 0.00 AC: 0 AN: 38356

South Asian (SAS) AF: 0.00 AC: 0 AN: 80450

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5280

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 855252

Other (OTH) AF: 0.0000195 AC: 1 AN: 51178

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.92
DANN	Benign	0.35
PhyloP100		0.026

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: rs3820908; hg19: chr2-197065964;