rs3219170

Variant names:

• chr2-201705509-A-G
• rs3219170
• NM_020919.4:c.4581-48T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-201705509-A-G
• chr2-201705509-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020919.4(ALS2):​c.4581-48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.922 in 1,485,640 control chromosomes in the GnomAD database, including 631,949 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (61068 hom., cov: 32)
  • Exomes 𝑓: 0.92 (570881 hom.)
• Consequence: ALS2 NM_020919.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.198
• 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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-201705509-A-G is Benign according to our data. Variant chr2-201705509-A-G is described in ClinVar as Benign. ClinVar VariationId is 261379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.962 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020919.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	NM_020919.4	MANE Select	c.4581-48T>C		intron	N/A	NP_065970.2
	ALS2	NM_001410975.1		c.4578-48T>C		intron	N/A	NP_001397904.1	A0A7P0T8F3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	ENST00000264276.11	TSL:1 MANE Select	c.4581-48T>C		intron	N/A	ENSP00000264276.6	Q96Q42-1
	ALS2	ENST00000680497.1		c.4683-48T>C		intron	N/A	ENSP00000505954.1	A0A7P0Z4F3
	ALS2	ENST00000905985.1		c.4674-48T>C		intron	N/A	ENSP00000576044.1

Frequencies

GnomAD3 genomes AF: 0.894 AC: 136002 AN: 152088 Hom.: 61021 Cov.: 32

Gnomad AFR AF: 0.819

Gnomad AMI AF: 0.981

Gnomad AMR AF: 0.882

Gnomad ASJ AF: 0.914

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.959

Gnomad FIN AF: 0.961

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.919

Gnomad OTH AF: 0.880

GnomAD2 exomes AF: 0.923 AC: 221992 AN: 240488 AF XY: 0.928

Gnomad AFR exome AF: 0.821

Gnomad AMR exome AF: 0.893

Gnomad ASJ exome AF: 0.916

Gnomad EAS exome AF: 0.986

Gnomad FIN exome AF: 0.954

Gnomad NFE exome AF: 0.921

Gnomad OTH exome AF: 0.920

GnomAD4 exome AF: 0.925 AC: 1233347 AN: 1333434 Hom.: 570881 Cov.: 19 AF XY: 0.927 AC XY: 621142 AN XY: 670362

African (AFR) AF: 0.825 AC: 25139 AN: 30478

American (AMR) AF: 0.890 AC: 39194 AN: 44058

Ashkenazi Jewish (ASJ) AF: 0.914 AC: 23084 AN: 25258

East Asian (EAS) AF: 0.991 AC: 38384 AN: 38744

South Asian (SAS) AF: 0.959 AC: 79229 AN: 82654

European-Finnish (FIN) AF: 0.954 AC: 50627 AN: 53080

Middle Eastern (MID) AF: 0.904 AC: 4352 AN: 4816

European-Non Finnish (NFE) AF: 0.923 AC: 921869 AN: 998496

Other (OTH) AF: 0.922 AC: 51469 AN: 55850

GnomAD4 genome AF: 0.894 AC: 136108 AN: 152206 Hom.: 61068 Cov.: 32 AF XY: 0.898 AC XY: 66792 AN XY: 74406

African (AFR) AF: 0.819 AC: 33995 AN: 41514

American (AMR) AF: 0.882 AC: 13486 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.914 AC: 3171 AN: 3470

East Asian (EAS) AF: 0.985 AC: 5106 AN: 5186

South Asian (SAS) AF: 0.959 AC: 4621 AN: 4818

European-Finnish (FIN) AF: 0.961 AC: 10196 AN: 10612

Middle Eastern (MID) AF: 0.878 AC: 258 AN: 294

European-Non Finnish (NFE) AF: 0.919 AC: 62524 AN: 68006

Other (OTH) AF: 0.880 AC: 1856 AN: 2108

Alfa AF: 0.904 Hom.: 12044

Bravo AF: 0.885

Asia WGS AF: 0.958 AC: 3327 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Amyotrophic lateral sclerosis type 2, juvenile (1)
-	-	1	Infantile-onset ascending hereditary spastic paralysis (1)
-	-	1	Juvenile primary lateral sclerosis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.1
DANN	Benign	0.78
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3219170; hg19: chr2-202570232;