5-74685406-C-G

Variant names:

• chr5-74685406-C-G
• NM_000521.4:c.146C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000521.4(HEXB):​c.146C>G​(p.Ser49Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HEXB NM_000521.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.46

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17444375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_000521.4	c.146C>G	p.Ser49Trp	missense_variant	Exon 1 of 14	ENST00000261416.12	NP_000512.2
HEXB	NM_001292004.2	c.-376-3922C>G		intron_variant	Intron 1 of 13		NP_001278933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000261416.12	c.146C>G	p.Ser49Trp	missense_variant	Exon 1 of 14	1	NM_000521.4	ENSP00000261416.7
HEXB	ENST00000511181.5	c.-376-3922C>G		intron_variant	Intron 1 of 13	1		ENSP00000426285.1
HEXB	ENST00000513079.5	n.211C>G		non_coding_transcript_exon_variant	Exon 1 of 6	2
HEXB	ENST00000515528.1	n.201C>G		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445012 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718016

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.0022	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	5.8
DANN	Benign	0.97
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.035	N
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.099	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.95	N
REVEL	Uncertain	0.38
Sift	Benign	0.036	D
Sift4G	Uncertain	0.017	D
Vest4		0.15
MutPred		0.41		Loss of disorder (P = 2e-04);
MVP		0.77
MPC		0.52
ClinPred		0.34	T
GERP RS		-0.92
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-73981231;