2-201761636-C-G

Variant names:

• chr2-201761636-C-G
• rs202084736
• NM_020919.4:c.358G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_020919.4(ALS2):​c.358G>C​(p.Ala120Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A120S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALS2 NM_020919.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.638
• 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 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_020919.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALS2	NM_020919.4	c.358G>C	p.Ala120Pro	missense_variant	Exon 4 of 34	ENST00000264276.11	NP_065970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11	c.358G>C	p.Ala120Pro	missense_variant	Exon 4 of 34	1	NM_020919.4	ENSP00000264276.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.4	M;M;.
PhyloP100		0.64
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.074	T;T;T
Sift4G	Benign	0.19	T;T;.
Polyphen		0.98	D;D;.
Vest4		0.66
MutPred		0.64		Gain of glycosylation at A120 (P = 0.0513);Gain of glycosylation at A120 (P = 0.0513);Gain of glycosylation at A120 (P = 0.0513);
MVP		0.89
MPC		0.80
ClinPred		0.71	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.62
gMVP		0.91
Mutation Taster		=68/32	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: rs202084736; hg19: chr2-202626359;