Genetic Variant HECTD2:p.Arg105Cys (chr10-91460471-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_182765.6(HECTD2):c.313C>T(p.Arg105Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 1,459,070 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R105H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

HECTD2
NM_182765.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.93

Variant links:

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 links:

ENSG00000289228 (HGNC:):

ENSG00000289228 links:

HECTD2-AS1 (HGNC:48679): (HECTD2 antisense RNA 1)

HECTD2-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30337492).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HECTD2	NM_182765.6 link	c.313C>T	p.Arg105Cys	missense_variant	Exon 3 of 21	ENST00000298068.10	NP_877497.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HECTD2	ENST00000298068.10 link	c.313C>T	p.Arg105Cys	missense_variant	Exon 3 of 21	1	NM_182765.6	ENSP00000298068.5		Q5U5R9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249462

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1459070

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725864

show subpopulations

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:

0.0000350

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000595

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.313C>T (p.R105C) alteration is located in exon 3 (coding exon 3) of the HECTD2 gene. This alteration results from a C to T substitution at nucleotide position 313, causing the arginine (R) at amino acid position 105 to be replaced by a cysteine (C). 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

0.14

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

T;.;T

Eigen

Benign

0.041

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.038

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.55

.;N;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.8

N;D;N

REVEL

Benign

0.12

Sift

Benign

0.049

D;D;D

Sift4G

Benign

0.086

T;T;T

Polyphen

0.032

B;.;B

Vest4

0.55

MutPred

0.29

Loss of MoRF binding (P = 0.0242);Loss of MoRF binding (P = 0.0242);Loss of MoRF binding (P = 0.0242);

MVP

0.22

MPC

0.67

ClinPred

0.43

GERP RS

5.4

Varity_R

0.19

gMVP

0.51

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over