chr5-74685138-GC-G

Position:

• chr5-74685138-GC-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001292004.2(HEXB):​c.-376-4189delC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23250 hom., cov: 0)
  • Exomes 𝑓: 0.56 (151750 hom.)
• Consequence: HEXB NM_001292004.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 5-74685138-GC-G is Benign according to our data. Variant chr5-74685138-GC-G is described in ClinVar as [Benign]. Clinvar id is 369507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXB	NM_001292004.2	c.-376-4189delC		intron_variant			NP_001278933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000511181.5	c.-376-4189delC		intron_variant		1		ENSP00000426285.1

Frequencies

GnomAD3 genomes AF: 0.550 AC: 83244 AN: 151264 Hom.: 23232 Cov.: 0

Gnomad AFR AF: 0.558

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.461

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.572

Gnomad OTH AF: 0.552

GnomAD4 exome AF: 0.563 AC: 530677 AN: 943042 Hom.: 151750 Cov.: 0 AF XY: 0.562 AC XY: 262327 AN XY: 466632

Gnomad4 AFR exome AF: 0.557

Gnomad4 AMR exome AF: 0.375

Gnomad4 ASJ exome AF: 0.577

Gnomad4 EAS exome AF: 0.477

Gnomad4 SAS exome AF: 0.566

Gnomad4 FIN exome AF: 0.623

Gnomad4 NFE exome AF: 0.567

Gnomad4 OTH exome AF: 0.554

GnomAD4 genome AF: 0.550 AC: 83297 AN: 151384 Hom.: 23250 Cov.: 0 AF XY: 0.549 AC XY: 40611 AN XY: 73934

Gnomad4 AFR AF: 0.558

Gnomad4 AMR AF: 0.412

Gnomad4 ASJ AF: 0.577

Gnomad4 EAS AF: 0.461

Gnomad4 SAS AF: 0.552

Gnomad4 FIN AF: 0.622

Gnomad4 NFE AF: 0.572

Gnomad4 OTH AF: 0.550

Alfa AF: 0.275 Hom.: 693

Asia WGS AF: 0.471 AC: 1634 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sandhoff disease Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 28, 2019	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs70976124; hg19: chr5-73980963;