10-91410550-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_182765.6(HECTD2):c.112G>C(p.Val38Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000772 in 1,296,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 7.7e-7 (0 hom.)
• Consequence: HECTD2 NM_182765.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.76

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05972582).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HECTD2	NM_182765.6	c.112G>C	p.Val38Leu	missense_variant	1/21	ENST00000298068.10
HECTD2-AS1	NR_024467.1	n.427-59671C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HECTD2	ENST00000298068.10	c.112G>C	p.Val38Leu	missense_variant	1/21	1	NM_182765.6	P4
	ENST00000688440.1	n.322-59671C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.72e-7 AC: 1 AN: 1296018 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 638216

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: 0.0000188

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

May 31, 2023

The c.112G>C (p.V38L) 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 112, causing the valine (V) at amino acid position 38 to be replaced by a leucine (L). 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	0.098
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.0084	T;.;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.63	T;T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.060	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.96	N;N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.12	N;N;N
REVEL	Benign	0.047
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.58	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.14
MutPred		0.18		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP		0.068
MPC		0.47
ClinPred		0.50	T
GERP RS		1.5
Varity_R		0.093
gMVP		0.10

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: chr10-93170307;