rs820878

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000521.4(HEXB):c.185T>C(p.Leu62Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.961 in 1,610,796 control chromosomes in the GnomAD database, including 744,515 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.97 ( 71637 hom., cov: 27)

Exomes 𝑓: 0.96 ( 672878 hom. )

Consequence

HEXB
NM_000521.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.769

Publications

44 publications found

Variant links:

Genes affected

HEXB (HGNC:4879): (hexosaminidase subunit beta) Hexosaminidase B is the beta subunit of the lysosomal enzyme beta-hexosaminidase that, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Beta-hexosaminidase is composed of two subunits, alpha and beta, which are encoded by separate genes. Both beta-hexosaminidase alpha and beta subunits are members of family 20 of glycosyl hydrolases. Mutations in the alpha or beta subunit genes lead to an accumulation of GM2 ganglioside in neurons and neurodegenerative disorders termed the GM2 gangliosidoses. Beta subunit gene mutations lead to Sandhoff disease (GM2-gangliosidosis type II). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

HEXB Gene-Disease associations (from GenCC):

Sandhoff disease
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Myriad Women’s Health, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

HEXB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.7268027E-7).

BP6

Variant 5-74685445-T-C is Benign according to our data. Variant chr5-74685445-T-C is described in ClinVar as Benign. ClinVar VariationId is 167173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.984 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000521.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXB	NM_000521.4	MANE Select	c.185T>C	p.Leu62Ser	missense	Exon 1 of 14	NP_000512.2	P07686
	HEXB	NM_001292004.2		c.-376-3883T>C		intron	N/A	NP_001278933.1	Q5URX0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HEXB	ENST00000261416.12	TSL:1 MANE Select	c.185T>C	p.Leu62Ser	missense	Exon 1 of 14	ENSP00000261416.7	P07686
HEXB	ENST00000511181.5	TSL:1	c.-376-3883T>C		intron	N/A	ENSP00000426285.1	Q5URX0
HEXB	ENST00000513079.5	TSL:2	n.250T>C		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes

AF:

0.972

AC:

147224

AN:

151436

Hom.:

71575

Cov.:

show subpopulations

Gnomad AFR

AF:

0.993

Gnomad AMI

AF:

0.977

Gnomad AMR

AF:

0.973

Gnomad ASJ

AF:

0.971

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.967

Gnomad FIN

AF:

0.978

Gnomad MID

AF:

0.968

Gnomad NFE

AF:

0.957

Gnomad OTH

AF:

0.971

GnomAD2 exomes

AF:

0.971

AC:

233065

AN:

239918

AF XY:

0.970

show subpopulations

Gnomad AFR exome

AF:

0.993

Gnomad AMR exome

AF:

0.983

Gnomad ASJ exome

AF:

0.972

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.980

Gnomad NFE exome

AF:

0.960

Gnomad OTH exome

AF:

0.969

GnomAD4 exome

AF:

0.960

AC:

1401122

AN:

1459242

Hom.:

672878

Cov.:

AF XY:

0.960

AC XY:

697092

AN XY:

725866

show subpopulations

African (AFR)

AF:

0.994

AC:

33185

AN:

33380

American (AMR)

AF:

0.981

AC:

43763

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.972

AC:

25317

AN:

26058

East Asian (EAS)

AF:

1.00

AC:

39610

AN:

39616

South Asian (SAS)

AF:

0.966

AC:

83157

AN:

86054

European-Finnish (FIN)

AF:

0.979

AC:

51121

AN:

52234

Middle Eastern (MID)

AF:

0.974

AC:

5614

AN:

5766

European-Non Finnish (NFE)

AF:

0.955

AC:

1061394

AN:

1111272

Other (OTH)

AF:

0.962

AC:

57961

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

3253

6506

9760

13013

16266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21620

43240

64860

86480

108100

<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

AF:

0.972

AC:

147345

AN:

151554

Hom.:

71637

Cov.:

AF XY:

0.973

AC XY:

72043

AN XY:

74014

show subpopulations

African (AFR)

AF:

0.993

AC:

41099

AN:

41408

American (AMR)

AF:

0.973

AC:

14812

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.971

AC:

3370

AN:

3470

East Asian (EAS)

AF:

0.999

AC:

5037

AN:

5040

South Asian (SAS)

AF:

0.967

AC:

4530

AN:

4686

European-Finnish (FIN)

AF:

0.978

AC:

10365

AN:

10600

Middle Eastern (MID)

AF:

0.966

AC:

284

AN:

294

European-Non Finnish (NFE)

AF:

0.957

AC:

64922

AN:

67824

Other (OTH)

AF:

0.971

AC:

2037

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

181

362

543

724

905

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

904

1808

2712

3616

4520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.964

Hom.:

126150

Bravo

AF:

0.973

TwinsUK

AF:

0.956

AC:

3546

ALSPAC

AF:

0.953

AC:

3674

ESP6500AA

AF:

0.990

AC:

4347

ESP6500EA

AF:

0.959

AC:

8237

ExAC

AF:

0.970

AC:

117228

Asia WGS

AF:

0.988

AC:

3435

AN:

3478

EpiCase

AF:

0.960

EpiControl

AF:

0.962

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Sandhoff disease (4)

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.44

CADD

Benign

4.1

(source)

DANN

Benign

0.70

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.00047

MetaRNN

Benign

7.7e-7

MetaSVM

Benign

-0.91

PhyloP100

0.77

PrimateAI

Uncertain

0.54

PROVEAN

Benign

2.7

REVEL

Benign

0.11

Sift

Benign

1.0

Sift4G

Benign

0.83

Vest4

0.025

MPC

0.24

ClinPred

0.0033

GERP RS

4.0

PromoterAI

0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.32

Mutation Taster

=94/6

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over