rs9288322

chr2-201727791-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020919.4(ALS2):c.2842-16G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00534 in 1,551,238 control chromosomes in the GnomAD database, including 354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (169 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (185 hom.)
• Consequence: ALS2 NM_020919.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.46

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-201727791-C-T is Benign according to our data. Variant chr2-201727791-C-T is described in ClinVar as [Benign]. Clinvar id is 261372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201727791-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALS2	NM_020919.4	c.2842-16G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000264276.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALS2	ENST00000264276.11	c.2842-16G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_020919.4	P4

Frequencies

GnomAD3 genomes AF: 0.0276 AC: 4201 AN: 152126 Hom.: 169 Cov.: 32

Gnomad AFR AF: 0.0955

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.00630 AC: 974 AN: 154538 Hom.: 42 AF XY: 0.00512 AC XY: 419 AN XY: 81792

Gnomad AFR exome AF: 0.0999

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.00176

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000307

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000450

Gnomad OTH exome AF: 0.00460

GnomAD4 exome AF: 0.00292 AC: 4087 AN: 1398994 Hom.: 185 Cov.: 33 AF XY: 0.00265 AC XY: 1829 AN XY: 690058

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.00555

Gnomad4 ASJ exome AF: 0.00171

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000202

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000192

Gnomad4 OTH exome AF: 0.00566

GnomAD4 genome AF: 0.0276 AC: 4204 AN: 152244 Hom.: 169 Cov.: 32 AF XY: 0.0265 AC XY: 1975 AN XY: 74432

Gnomad4 AFR AF: 0.0953

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0157 Hom.: 23

Bravo AF: 0.0316

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Infantile-onset ascending hereditary spastic paralysis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.053
Dann	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs9288322; hg19: chr2-202592514;