5-74684974-G-C

Variant names:

• chr5-74684974-G-C
• rs2936918
• ENST00000511181.5:c.-376-4354G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001292004.2(HEXB):​c.-376-4354G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 152,026 control chromosomes in the GnomAD database, including 21,751 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.53 (21751 hom., cov: 32)
• Consequence: HEXB NM_001292004.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.276
• Publications: 3 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen, Genomics England PanelApp, Myriad Women’s Health

ENSG00000306131 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 5-74684974-G-C is Benign according to our data. Variant chr5-74684974-G-C is described in ClinVar as [Benign]. Clinvar id is 680596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_001292004.2	c.-376-4354G>C		intron_variant	Intron 1 of 13		NP_001278933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000511181.5	c.-376-4354G>C		intron_variant	Intron 1 of 13	1		ENSP00000426285.1
ENSG00000306131	ENST00000815555.1	n.112+24C>G		intron_variant	Intron 1 of 1
HEXB	ENST00000513079.5	n.-222G>C		upstream_gene_variant		2
HEXB	ENST00000515528.1	n.-232G>C		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80434 AN: 151910 Hom.: 21738 Cov.: 32

Gnomad AFR AF: 0.481

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.573

Gnomad OTH AF: 0.534

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.529 AC: 80466 AN: 152026 Hom.: 21751 Cov.: 32 AF XY: 0.530 AC XY: 39367 AN XY: 74306

African (AFR) AF: 0.481 AC: 19953 AN: 41454

American (AMR) AF: 0.405 AC: 6184 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 2005 AN: 3472

East Asian (EAS) AF: 0.465 AC: 2395 AN: 5154

South Asian (SAS) AF: 0.553 AC: 2660 AN: 4814

European-Finnish (FIN) AF: 0.625 AC: 6612 AN: 10574

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.573 AC: 38940 AN: 67958

Other (OTH) AF: 0.533 AC: 1127 AN: 2116

Alfa AF: 0.410 Hom.: 1108

Bravo AF: 0.508

Asia WGS AF: 0.469 AC: 1631 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.2
DANN	Benign	0.53
PhyloP100		-0.28
PromoterAI		-0.016	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2936918; hg19: chr5-73980799;