rs3219154

Positions:

• chr2-201761714-T-A
• chr2-201761714-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020919.4(ALS2):​c.280A>T​(p.Ile94Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. I94V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALS2 NM_020919.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.888

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3457517).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALS2	NM_020919.4	c.280A>T	p.Ile94Phe	missense_variant	4/34	ENST00000264276.11	NP_065970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11	c.280A>T	p.Ile94Phe	missense_variant	4/34	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	Benign	0.10
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.054
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	T;T;T;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.2	M;M;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N;D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;.;.
Polyphen		0.37	B;P;.;.
Vest4		0.20
MutPred		0.37		Gain of catalytic residue at I94 (P = 0.0121);Gain of catalytic residue at I94 (P = 0.0121);Gain of catalytic residue at I94 (P = 0.0121);Gain of catalytic residue at I94 (P = 0.0121);
MVP		0.86
MPC		0.41
ClinPred		0.67	D
GERP RS		2.9
Varity_R		0.13
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs3219154; hg19: chr2-202626437;