10-91485272-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_182765.6(HECTD2):c.1063C>G(p.His355Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,442,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HECTD2 NM_182765.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.38

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38323566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HECTD2	NM_182765.6	c.1063C>G	p.His355Asp	missense_variant	10/21	ENST00000298068.10
HECTD2-AS1	NR_024467.1	n.426+39756G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HECTD2	ENST00000298068.10	c.1063C>G	p.His355Asp	missense_variant	10/21	1	NM_182765.6	P4
	ENST00000688440.1	n.321+39756G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442624 Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1 AN XY: 717494

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: 9.05e-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

Aug 17, 2021

The c.1063C>G (p.H355D) alteration is located in exon 10 (coding exon 10) of the HECTD2 gene. This alteration results from a C to G substitution at nucleotide position 1063, causing the histidine (H) at amino acid position 355 to be replaced by an aspartic acid (D). 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	0.32
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.030	T;T;.
Eigen	Benign	0.049
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.34	T;T;T
Sift4G	Benign	0.074	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.59
MutPred		0.45		Gain of helix (P = 0.0325);.;.;
MVP		0.32
MPC		1.6
ClinPred		0.80	D
GERP RS		5.6
Varity_R		0.29
gMVP		0.92

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: chr10-93245029;