NM_001348768.2:c.2741C>A

Variant names:

• chr2-196306561-G-T
• NM_001348768.2:c.2741C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001348768.2(HECW2):​c.2741C>A​(p.Thr914Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,584 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HECW2 NM_001348768.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.28

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the HECW2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 62 curated benign missense variants. Gene score misZ: 3.3052 (above the threshold of 3.09). Trascript score misZ: 3.6429 (above the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder with hypotonia, seizures, and absent language, complex neurodevelopmental disorder.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HECW2	NM_001348768.2	c.2741C>A	p.Thr914Lys	missense_variant	Exon 13 of 29	ENST00000644978.2	NP_001335697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HECW2	ENST00000644978.2	c.2741C>A	p.Thr914Lys	missense_variant	Exon 13 of 29		NM_001348768.2	ENSP00000495418.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460584 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726612

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	.;D;.;D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.50	D;D;D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.8	L;.;L;L
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.6	D;.;.;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.0070	D;.;.;.
Sift4G	Uncertain	0.031	D;.;.;.
Polyphen		0.55	P;.;P;P
Vest4		0.54
MutPred		0.40		Gain of ubiquitination at T914 (P = 0.0325);.;Gain of ubiquitination at T914 (P = 0.0325);Gain of ubiquitination at T914 (P = 0.0325);
MVP		0.87
MPC		0.41
ClinPred		0.87	D
GERP RS		5.7
Varity_R		0.20
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-197171285;