NM_020919.4:c.280A>G

Variant names:

• chr2-201761714-T-C
• rs3219154
• NM_020919.4:c.280A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020919.4(ALS2):​c.280A>G​(p.Ile94Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,613,992 control chromosomes in the GnomAD database, including 740 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I94S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.033 (97 hom., cov: 32)
  • Exomes 𝑓: 0.028 (643 hom.)
• Consequence: ALS2 NM_020919.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.888
• Publications: 18 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023296773).
• BP6: Variant 2-201761714-T-C is Benign according to our data. Variant chr2-201761714-T-C is described in ClinVar as Benign. ClinVar VariationId is 261370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0333 (5069/152108) while in subpopulation AFR AF = 0.0518 (2148/41482). AF 95% confidence interval is 0.05. There are 97 homozygotes in GnomAd4. There are 2412 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 97 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.280A>G	p.Ile94Val	missense	Exon 4 of 34	NP_065970.2
	ALS2	NM_001410975.1		c.280A>G	p.Ile94Val	missense	Exon 4 of 34	NP_001397904.1	A0A7P0T8F3
	ALS2	NM_001135745.2		c.280A>G	p.Ile94Val	missense	Exon 4 of 4	NP_001129217.1	Q96Q42-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	ENST00000264276.11	TSL:1 MANE Select	c.280A>G	p.Ile94Val	missense	Exon 4 of 34	ENSP00000264276.6	Q96Q42-1
	ALS2	ENST00000467448.5	TSL:1	c.280A>G	p.Ile94Val	missense	Exon 4 of 4	ENSP00000429223.1	Q96Q42-2
	ALS2	ENST00000482789.6	TSL:1	n.622A>G		non_coding_transcript_exon	Exon 4 of 13

Frequencies

GnomAD3 genomes AF: 0.0333 AC: 5059 AN: 151990 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.0519

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.0241

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0259

GnomAD2 exomes AF: 0.0251 AC: 6235 AN: 248818 AF XY: 0.0250

Gnomad AFR exome AF: 0.0539

Gnomad AMR exome AF: 0.0145

Gnomad ASJ exome AF: 0.0480

Gnomad EAS exome AF: 0.000556

Gnomad FIN exome AF: 0.0220

Gnomad NFE exome AF: 0.0263

Gnomad OTH exome AF: 0.0286

GnomAD4 exome AF: 0.0284 AC: 41510 AN: 1461884 Hom.: 643 Cov.: 38 AF XY: 0.0280 AC XY: 20344 AN XY: 727244

African (AFR) AF: 0.0498 AC: 1667 AN: 33480

American (AMR) AF: 0.0148 AC: 663 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0488 AC: 1275 AN: 26136

East Asian (EAS) AF: 0.000453 AC: 18 AN: 39700

South Asian (SAS) AF: 0.0257 AC: 2214 AN: 86258

European-Finnish (FIN) AF: 0.0224 AC: 1199 AN: 53418

Middle Eastern (MID) AF: 0.0186 AC: 107 AN: 5768

European-Non Finnish (NFE) AF: 0.0294 AC: 32680 AN: 1112004

Other (OTH) AF: 0.0279 AC: 1687 AN: 60396

GnomAD4 genome AF: 0.0333 AC: 5069 AN: 152108 Hom.: 97 Cov.: 32 AF XY: 0.0324 AC XY: 2412 AN XY: 74366

African (AFR) AF: 0.0518 AC: 2148 AN: 41482

American (AMR) AF: 0.0240 AC: 367 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 171 AN: 3468

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5176

South Asian (SAS) AF: 0.0243 AC: 117 AN: 4824

European-Finnish (FIN) AF: 0.0241 AC: 254 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0283 AC: 1926 AN: 68006

Other (OTH) AF: 0.0304 AC: 64 AN: 2108

Alfa AF: 0.0292 Hom.: 300

Bravo AF: 0.0330

TwinsUK AF: 0.0329 AC: 122

ALSPAC AF: 0.0306 AC: 118

ESP6500AA AF: 0.0501 AC: 198

ESP6500EA AF: 0.0256 AC: 213

ExAC AF: 0.0249 AC: 3008

Asia WGS AF: 0.0420 AC: 146 AN: 3478

EpiCase AF: 0.0260

EpiControl AF: 0.0249

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	ALS2-related disorder (1)
-	-	1	Amyotrophic lateral sclerosis type 2, juvenile (1)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Infantile-onset ascending hereditary spastic paralysis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Benign	0.65
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.15	N
PhyloP100		0.89
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.020
MPC		0.19
ClinPred		0.00064	T
GERP RS		2.9
Varity_R		0.014
gMVP		0.28
Mutation Taster		=99/1	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: rs3219154; hg19: chr2-202626437; COSMIC: COSV51887162; COSMIC: COSV51887162;