NM_000405.5:c.164C>G

Variant names:

• chr5-151259837-C-G
• rs730882196
• NM_000405.5:c.164C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000405.5(GM2A):​c.164C>G​(p.Pro55Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P55L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GM2A NM_000405.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.50
• Publications: 0 publications found

Genes affected

GM2A (HGNC:4367): (ganglioside GM2 activator) This gene encodes a small glycolipid transport protein which acts as a substrate specific co-factor for the lysosomal enzyme beta-hexosaminidase A. Beta-hexosaminidase A, together with GM2 ganglioside activator, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene result in GM2-gangliosidosis type AB or the AB variant of Tay-Sachs disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2009]

GM2A Gene-Disease associations (from GenCC):

• Tay-Sachs disease AB variant

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000405.5. 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
	GM2A	NM_000405.5	MANE Select	c.164C>G	p.Pro55Arg	missense	Exon 2 of 4	NP_000396.2
	GM2A	NM_001167607.3		c.164C>G	p.Pro55Arg	missense	Exon 2 of 4	NP_001161079.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GM2A	ENST00000357164.4	TSL:1 MANE Select	c.164C>G	p.Pro55Arg	missense	Exon 2 of 4	ENSP00000349687.3	P17900
	GM2A	ENST00000523004.1	TSL:1	c.38C>G	p.Pro13Arg	missense	Exon 1 of 2	ENSP00000430541.1	H0YBY3
	GM2A	ENST00000523466.5	TSL:3	c.209C>G	p.Pro70Arg	missense	Exon 3 of 4	ENSP00000429100.1	E5RJD0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.5
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-8.9	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.53		Gain of solvent accessibility (P = 0.0216)
MVP		0.92
MPC		0.42
ClinPred		1.0	D
GERP RS		4.5
PromoterAI		0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.95
Mutation Taster		=17/83	disease causing

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

Other links and lift over

dbSNP: rs730882196; hg19: chr5-150639398;