rs970595

Variant names:

• chr2-201772188-T-C
• rs970595
• NM_020919.4:c.-60-3243A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020919.4(ALS2):​c.-60-3243A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 152,060 control chromosomes in the GnomAD database, including 13,423 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.38 (13423 hom., cov: 32)
• Consequence: ALS2 NM_020919.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0350
• Publications: 9 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALS2	NM_020919.4	c.-60-3243A>G		intron_variant	Intron 1 of 33	ENST00000264276.11	NP_065970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALS2	ENST00000264276.11	c.-60-3243A>G		intron_variant	Intron 1 of 33	1	NM_020919.4	ENSP00000264276.6

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57251 AN: 151942 Hom.: 13425 Cov.: 32

Gnomad AFR AF: 0.0941

Gnomad AMI AF: 0.639

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.517

Gnomad EAS AF: 0.351

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.506

Gnomad OTH AF: 0.404

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.376 AC: 57250 AN: 152060 Hom.: 13423 Cov.: 32 AF XY: 0.377 AC XY: 27993 AN XY: 74324

African (AFR) AF: 0.0939 AC: 3896 AN: 41512

American (AMR) AF: 0.477 AC: 7279 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 1792 AN: 3468

East Asian (EAS) AF: 0.352 AC: 1816 AN: 5164

South Asian (SAS) AF: 0.373 AC: 1794 AN: 4814

European-Finnish (FIN) AF: 0.444 AC: 4684 AN: 10538

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.506 AC: 34414 AN: 67978

Other (OTH) AF: 0.403 AC: 851 AN: 2112

Alfa AF: 0.475 Hom.: 35775

Bravo AF: 0.365

Asia WGS AF: 0.296 AC: 1029 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.8
DANN	Benign	0.58
PhyloP100		0.035
Mutation Taster		=100/0	polymorphism (auto)

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: rs970595; hg19: chr2-202636911;