10-91425297-C-T

Position:

• chr10-91425297-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182765.6(HECTD2):​c.155C>T​(p.Ala52Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HECTD2 NM_182765.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.12

Genes affected

HECTD2 (HGNC:26736): (HECT domain E3 ubiquitin protein ligase 2) Predicted to enable ubiquitin-protein transferase activity. Predicted to be involved in protein ubiquitination. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

HECTD2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13292617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HECTD2	NM_182765.6	c.155C>T	p.Ala52Val	missense_variant	2/21	ENST00000298068.10	NP_877497.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HECTD2	ENST00000298068.10	c.155C>T	p.Ala52Val	missense_variant	2/21	1	NM_182765.6	ENSP00000298068.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1388244 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 689542

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2024

The c.155C>T (p.A52V) alteration is located in exon 2 (coding exon 2) of the HECTD2 gene. This alteration results from a C to T substitution at nucleotide position 155, causing the alanine (A) at amino acid position 52 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T;.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.80	N;N;N
REVEL	Benign	0.012
Sift	Benign	0.044	D;T;D
Sift4G	Benign	0.24	T;T;T
Polyphen		0.012	B;.;B
Vest4		0.26
MutPred		0.23		Gain of methylation at K53 (P = 0.0379);Gain of methylation at K53 (P = 0.0379);Gain of methylation at K53 (P = 0.0379);
MVP		0.082
MPC		0.53
ClinPred		0.74	D
GERP RS		4.5
Varity_R		0.12
gMVP		0.30

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

LitVar

Other links and lift over

dbSNP: rs1208824130; hg19: chr10-93185054;