10-91496341-T-C

Position:

• chr10-91496341-T-C

Variant summary

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

The NM_182765.6(HECTD2):​c.1649T>C​(p.Val550Ala) 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: 3.42

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]

(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=0.15824035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HECTD2	NM_182765.6	c.1649T>C	p.Val550Ala	missense_variant	15/21	ENST00000298068.10	NP_877497.4
HECTD2-AS1	NR_024467.1	n.426+28687A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HECTD2	ENST00000298068.10	c.1649T>C	p.Val550Ala	missense_variant	15/21	1	NM_182765.6	ENSP00000298068	P4
	ENST00000688440.1	n.321+28687A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460080 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726390

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

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

Apr 12, 2024

The c.1649T>C (p.V550A) alteration is located in exon 15 (coding exon 15) of the HECTD2 gene. This alteration results from a T to C substitution at nucleotide position 1649, causing the valine (V) at amino acid position 550 to be replaced by an alanine (A). 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	0.24
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.010	T;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.039
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.70	.;N;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.047
Sift	Benign	0.27	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.0090	B;B;.
Vest4		0.24
MutPred		0.60		Loss of stability (P = 0.0276);.;.;
MVP		0.15
MPC		1.4
ClinPred		0.77	D
GERP RS		5.2
Varity_R		0.11
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs943091079; hg19: chr10-93256098;