rs758889641

chr2-201707890-C-Achr2-201707890-C-T

Variant summary

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

The NM_020919.4(ALS2):c.4382G>T(p.Arg1461Leu) 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 1,461,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1461Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALS2 NM_020919.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74

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=0.31484634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALS2	NM_020919.4	c.4382G>T	p.Arg1461Leu	missense_variant	28/34	ENST00000264276.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALS2	ENST00000264276.11	c.4382G>T	p.Arg1461Leu	missense_variant	28/34	1	NM_020919.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461192 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726902

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.098	T
Eigen	Benign	0.017
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.96	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.22
Sift	Benign	0.27	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.57
MutPred		0.18		Loss of solvent accessibility (P = 0.0299);
MVP		0.68
MPC		0.29
ClinPred		0.64	D
GERP RS		5.9
Varity_R		0.24
gMVP		0.31

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: rs758889641; hg19: chr2-202572613;