chr2-201700958-G-A

Variant names:

• chr2-201700958-G-A
• rs3219174
• NM_020919.4:c.*893C>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.*893C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0588 in 152,336 control chromosomes in the GnomAD database, including 373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (373 hom., cov: 32)
  • Exomes 𝑓: 0.064 (0 hom.)
• Consequence: ALS2 NM_020919.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.415
• Publications: 7 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=-0.85).
• BP6: Variant 2-201700958-G-A is Benign according to our data. Variant chr2-201700958-G-A is described in ClinVar as Benign. ClinVar VariationId is 333577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.224 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.*893C>T		3_prime_UTR	Exon 34 of 34	NP_065970.2
	ALS2	NM_001410975.1		c.*893C>T		3_prime_UTR	Exon 34 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.*893C>T		3_prime_UTR	Exon 34 of 34	ENSP00000264276.6	Q96Q42-1
	ALS2	ENST00000680497.1		c.*893C>T		3_prime_UTR	Exon 34 of 34	ENSP00000505954.1	A0A7P0Z4F3
	ALS2	ENST00000905985.1		c.*893C>T		3_prime_UTR	Exon 35 of 35	ENSP00000576044.1

Frequencies

GnomAD3 genomes AF: 0.0589 AC: 8959 AN: 152108 Hom.: 373 Cov.: 32

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0317

Gnomad ASJ AF: 0.0600

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0900

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0605

Gnomad OTH AF: 0.0564

GnomAD4 exome AF: 0.0636 AC: 7 AN: 110 Hom.: 0 Cov.: 0 AF XY: 0.0571 AC XY: 4 AN XY: 70

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0660 AC: 7 AN: 106

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.0588 AC: 8951 AN: 152226 Hom.: 373 Cov.: 32 AF XY: 0.0622 AC XY: 4630 AN XY: 74434

African (AFR) AF: 0.0291 AC: 1208 AN: 41546

American (AMR) AF: 0.0316 AC: 483 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0600 AC: 208 AN: 3468

East Asian (EAS) AF: 0.235 AC: 1215 AN: 5164

South Asian (SAS) AF: 0.103 AC: 495 AN: 4816

European-Finnish (FIN) AF: 0.0900 AC: 955 AN: 10606

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0605 AC: 4114 AN: 68012

Other (OTH) AF: 0.0558 AC: 118 AN: 2116

Alfa AF: 0.0605 Hom.: 610

Bravo AF: 0.0534

Asia WGS AF: 0.159 AC: 554 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	ALS2-related disorder (1)
-	-	1	Amyotrophic lateral sclerosis type 2, juvenile (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.1
DANN	Benign	0.60
PhyloP100		0.41
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: rs3219174; hg19: chr2-202565681;