Genetic Variant HECTD2:p.Ser60Arg (chr10-91425322-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS2

The NM_182765.6(HECTD2):c.180C>A(p.Ser60Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000036 in 1,388,968 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: 0.0000036 ( 0 hom. )

Consequence

HECTD2
NM_182765.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.93

Publications

0 publications found

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:

HECTD2-AS1 (HGNC:):

HECTD2-AS1 links:

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

HECTD2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.111113995).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182765.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HECTD2	NM_182765.6	MANE Select	c.180C>A	p.Ser60Arg	missense	Exon 2 of 21	NP_877497.4	Q5U5R9-1
HECTD2	NM_001284274.3		c.180C>A	p.Ser60Arg	missense	Exon 2 of 22	NP_001271203.2	E7ERR3
HECTD2	NM_173497.4		c.180C>A	p.Ser60Arg	missense	Exon 2 of 5	NP_775768.4	Q5U5R9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HECTD2	ENST00000298068.10	TSL:1 MANE Select	c.180C>A	p.Ser60Arg	missense	Exon 2 of 21	ENSP00000298068.5	Q5U5R9-1
HECTD2	ENST00000446394.5	TSL:2	c.180C>A	p.Ser60Arg	missense	Exon 2 of 22	ENSP00000401023.1	E7ERR3
HECTD2	ENST00000371681.8	TSL:2	c.180C>A	p.Ser60Arg	missense	Exon 2 of 5	ENSP00000360746.4	Q5U5R9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000434

AC:

AN:

230270

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000933

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000360

AC:

AN:

1388968

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

690386

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31528

American (AMR)

AF:

0.00

AC:

AN:

40228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24540

East Asian (EAS)

AF:

0.00

AC:

AN:

37424

South Asian (SAS)

AF:

0.00

AC:

AN:

73664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50458

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5490

European-Non Finnish (NFE)

AF:

0.00000468

AC:

AN:

1069262

Other (OTH)

AF:

0.00

AC:

AN:

56374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.020

Eigen

Benign

0.036

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.0094

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.90

PhyloP100

2.9

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.3

REVEL

Benign

0.083

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0060

Polyphen

0.0010

Vest4

0.35

MutPred

0.35

Gain of MoRF binding (P = 0.0084)

MVP

0.093

MPC

0.92

ClinPred

0.85

GERP RS

4.4

Varity_R

0.33

gMVP

0.58

Mutation Taster

=55/45

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over