2-201702041-C-T

Position:

• chr2-201702041-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.4936-152G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 720,062 control chromosomes in the GnomAD database, including 33,158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6372 hom., cov: 25)
  • Exomes 𝑓: 0.28 (26786 hom.)
• Consequence: ALS2 NM_020919.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.139

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-201702041-C-T is Benign according to our data. Variant chr2-201702041-C-T is described in ClinVar as [Benign]. Clinvar id is 1230069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALS2	NM_020919.4	c.4936-152G>A		intron_variant		ENST00000264276.11	NP_065970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11	c.4936-152G>A		intron_variant		1	NM_020919.4	ENSP00000264276.6

Frequencies

GnomAD3 genomes AF: 0.278 AC: 41242 AN: 148360 Hom.: 6360 Cov.: 25

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.628

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.264

GnomAD4 exome AF: 0.278 AC: 158666 AN: 571584 Hom.: 26786 AF XY: 0.286 AC XY: 86308 AN XY: 302060

Gnomad4 AFR exome AF: 0.315

Gnomad4 AMR exome AF: 0.181

Gnomad4 ASJ exome AF: 0.270

Gnomad4 EAS exome AF: 0.638

Gnomad4 SAS exome AF: 0.462

Gnomad4 FIN exome AF: 0.313

Gnomad4 NFE exome AF: 0.220

Gnomad4 OTH exome AF: 0.280

GnomAD4 genome AF: 0.278 AC: 41298 AN: 148478 Hom.: 6372 Cov.: 25 AF XY: 0.286 AC XY: 20651 AN XY: 72162

Gnomad4 AFR AF: 0.314

Gnomad4 AMR AF: 0.190

Gnomad4 ASJ AF: 0.266

Gnomad4 EAS AF: 0.628

Gnomad4 SAS AF: 0.488

Gnomad4 FIN AF: 0.332

Gnomad4 NFE AF: 0.229

Gnomad4 OTH AF: 0.268

Alfa AF: 0.232 Hom.: 5737

Bravo AF: 0.268

Asia WGS AF: 0.569 AC: 1975 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.9
DANN	Benign	0.74

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: rs3731707; hg19: chr2-202566764;