rs753947052

Variant names:

• chr2-201746595-T-C
• rs753947052
• NM_020919.4:c.1969A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000264276.11(ALS2):​c.1969A>G​(p.Lys657Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ALS2 ENST00000264276.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.19
• Publications: 0 publications found

Genes affected

ALS2 (HGNC:443): (alsin Rho guanine nucleotide exchange factor ALS2) The protein encoded by this gene contains an ATS1/RCC1-like domain, a RhoGEF domain, and a vacuolar protein sorting 9 (VPS9) domain, all of which are guanine-nucleotide exchange factors that activate members of the Ras superfamily of GTPases. The protein functions as a guanine nucleotide exchange factor for the small GTPase RAB5. The protein localizes with RAB5 on early endosomal compartments, and functions as a modulator for endosomal dynamics. Mutations in this gene result in several forms of juvenile lateral sclerosis and infantile-onset ascending spastic paralysis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

ALS2 Gene-Disease associations (from GenCC):

• ALS2-related motor neuron disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• amyotrophic lateral sclerosis type 2, juvenile

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• infantile-onset ascending hereditary spastic paralysis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• juvenile primary lateral sclerosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23887995).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000264276.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	NM_020919.4	MANE Select	c.1969A>G	p.Lys657Glu	missense	Exon 9 of 34	NP_065970.2
	ALS2	NM_001410975.1		c.1969A>G	p.Lys657Glu	missense	Exon 9 of 34	NP_001397904.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	ENST00000264276.11	TSL:1 MANE Select	c.1969A>G	p.Lys657Glu	missense	Exon 9 of 34	ENSP00000264276.6
	ALS2	ENST00000482789.6	TSL:1	n.2311A>G		non_coding_transcript_exon	Exon 9 of 13
	ALS2	ENST00000482891.6	TSL:1	n.2311A>G		non_coding_transcript_exon	Exon 9 of 22

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000801 AC: 2 AN: 249550 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Infantile-onset ascending hereditary spastic paralysis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.032
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.25
Sift	Benign	0.82	T
Sift4G	Benign	0.77	T
Polyphen		0.054	B
Vest4		0.48
MutPred		0.41		Loss of ubiquitination at K657 (P = 0.0037)
MVP		0.76
MPC		0.33
ClinPred		0.22	T
GERP RS		5.8
Varity_R		0.076
gMVP		0.41
Mutation Taster		=87/13	polymorphism

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: rs753947052; hg19: chr2-202611318;