2-201757440-C-T

Variant names:

• chr2-201757440-C-T
• rs373603368
• NM_020919.4:c.1433G>A

Variant summary

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

The NM_020919.4(ALS2):​c.1433G>A​(p.Gly478Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,582 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign 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. G478A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALS2 NM_020919.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020919.4. 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.1433G>A	p.Gly478Asp	missense	Exon 5 of 34	NP_065970.2
	ALS2	NM_001410975.1		c.1433G>A	p.Gly478Asp	missense	Exon 5 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.1433G>A	p.Gly478Asp	missense	Exon 5 of 34	ENSP00000264276.6
	ALS2	ENST00000482789.6	TSL:1	n.1775G>A		non_coding_transcript_exon	Exon 5 of 13
	ALS2	ENST00000482891.6	TSL:1	n.1775G>A		non_coding_transcript_exon	Exon 5 of 22

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461582 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727102

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111808

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.4
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.12
Sift	Benign	0.15	T
Sift4G	Benign	0.063	T
Polyphen		0.76	P
Vest4		0.64
MutPred		0.26		Gain of sheet (P = 0.0028)
MVP		0.71
MPC		0.59
ClinPred		0.78	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.45
Mutation Taster		=84/16	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: rs373603368; hg19: chr2-202622163; COSMIC: COSV51883937; COSMIC: COSV51883937;