10-91410526-G-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.88G>C(p.Glu30Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000755 in 1,324,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 7.5e-7 (0 hom.)
• Consequence: HECTD2 NM_182765.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17

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=0.09713298).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HECTD2	NM_182765.6	c.88G>C	p.Glu30Gln	missense_variant	1/21	ENST00000298068.10
HECTD2-AS1	NR_024467.1	n.427-59647C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HECTD2	ENST00000298068.10	c.88G>C	p.Glu30Gln	missense_variant	1/21	1	NM_182765.6	P4
	ENST00000688440.1	n.322-59647C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.55e-7 AC: 1 AN: 1324898 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 654228

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: 9.53e-7

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

Feb 21, 2024

The c.88G>C (p.E30Q) alteration is located in exon 1 (coding exon 1) of the HECTD2 gene. This alteration results from a G to C substitution at nucleotide position 88, causing the glutamic acid (E) at amino acid position 30 to be replaced by a glutamine (Q). 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	0.12
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0094	T;.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.0090	N
LIST_S2	Benign	0.70	T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.097	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.75	N;N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.37	N;N;N
REVEL	Benign	0.021
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.48	T;T;T
Polyphen		0.028	B;.;B
Vest4		0.12
MutPred		0.089		Gain of methylation at K33 (P = 0.1108);Gain of methylation at K33 (P = 0.1108);Gain of methylation at K33 (P = 0.1108);
MVP		0.15
MPC		0.47
ClinPred		0.19	T
GERP RS		2.0
Varity_R		0.16
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-93170283;