rs773628251

Variant names:

• chr2-201733356-TCAGTATTTC-T
• rs773628251
• NM_020919.4:c.2491_2499delGAAATACTG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM4 PP3 BP6 BS2

The NM_020919.4(ALS2):​c.2491_2499delGAAATACTG​(p.Glu831_Leu833del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000326 in 1,613,668 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (3 hom.)
• Consequence: ALS2 NM_020919.4 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 8.43
• Publications: 0 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• juvenile primary lateral sclerosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_020919.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 2-201733356-TCAGTATTTC-T is Benign according to our data. Variant chr2-201733356-TCAGTATTTC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446821.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.2491_2499delGAAATACTG	p.Glu831_Leu833del	conservative_inframe_deletion	Exon 13 of 34	NP_065970.2
	ALS2	NM_001410975.1		c.2491_2499delGAAATACTG	p.Glu831_Leu833del	conservative_inframe_deletion	Exon 13 of 34	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.2491_2499delGAAATACTG	p.Glu831_Leu833del	conservative_inframe_deletion	Exon 13 of 34	ENSP00000264276.6	Q96Q42-1
	ALS2	ENST00000482789.6	TSL:1	n.2833_2841delGAAATACTG		non_coding_transcript_exon	Exon 13 of 13
	ALS2	ENST00000482891.6	TSL:1	n.2833_2841delGAAATACTG		non_coding_transcript_exon	Exon 13 of 22

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152178 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000846 AC: 211 AN: 249312 AF XY: 0.000850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000743

Gnomad NFE exome AF: 0.00168

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.000349 AC: 510 AN: 1461490 Hom.: 3 AF XY: 0.000338 AC XY: 246 AN XY: 727058

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.000993 AC: 53 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000339 AC: 377 AN: 1111824

Other (OTH) AF: 0.00132 AC: 80 AN: 60378

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152178 Hom.: 1 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000106

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	ALS2-related disorder (1)
-	-	1	Infantile-onset ascending hereditary spastic paralysis (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.4
Mutation Taster		=70/130	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs773628251; hg19: chr2-202598079;