chr2-201761519-C-T

Variant names:

• chr2-201761519-C-T
• rs3219155
• NM_020919.4:c.475G>A

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.475G>A​(p.Glu159Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00231 in 1,613,970 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (114 hom.)
• Consequence: ALS2 NM_020919.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.88
• Publications: 14 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=0.006737292).
• BP6: Variant 2-201761519-C-T is Benign according to our data. Variant chr2-201761519-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0579 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.475G>A	p.Glu159Lys	missense	Exon 4 of 34	NP_065970.2
	ALS2	NM_001410975.1		c.475G>A	p.Glu159Lys	missense	Exon 4 of 34	NP_001397904.1	A0A7P0T8F3
	ALS2	NM_001135745.2		c.475G>A	p.Glu159Lys	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.475G>A	p.Glu159Lys	missense	Exon 4 of 34	ENSP00000264276.6	Q96Q42-1
	ALS2	ENST00000467448.5	TSL:1	c.475G>A	p.Glu159Lys	missense	Exon 4 of 4	ENSP00000429223.1	Q96Q42-2
	ALS2	ENST00000482789.6	TSL:1	n.817G>A		non_coding_transcript_exon	Exon 4 of 13

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152208 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0275

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00905 AC: 2259 AN: 249494 AF XY: 0.00681

Gnomad AFR exome AF: 0.000839

Gnomad AMR exome AF: 0.0597

Gnomad ASJ exome AF: 0.00626

Gnomad EAS exome AF: 0.00312

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000795

Gnomad OTH exome AF: 0.00809

GnomAD4 exome AF: 0.00219 AC: 3201 AN: 1461644 Hom.: 114 Cov.: 38 AF XY: 0.00191 AC XY: 1389 AN XY: 727060

African (AFR) AF: 0.000657 AC: 22 AN: 33476

American (AMR) AF: 0.0597 AC: 2672 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00597 AC: 156 AN: 26134

East Asian (EAS) AF: 0.00232 AC: 92 AN: 39678

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000621 AC: 69 AN: 1111814

Other (OTH) AF: 0.00270 AC: 163 AN: 60382

GnomAD4 genome AF: 0.00343 AC: 522 AN: 152326 Hom.: 12 Cov.: 32 AF XY: 0.00348 AC XY: 259 AN XY: 74494

African (AFR) AF: 0.00108 AC: 45 AN: 41572

American (AMR) AF: 0.0279 AC: 427 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.00231 AC: 12 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00248 Hom.: 25

Bravo AF: 0.00689

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000962 AC: 4

ESP6500EA AF: 0.000594 AC: 5

ExAC AF: 0.00671 AC: 812

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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)
-	-	1	Juvenile primary lateral sclerosis;C1859807:Amyotrophic lateral sclerosis type 2, juvenile;C2931441:Infantile-onset ascending hereditary spastic paralysis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0067	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.36
Sift	Benign	0.10	T
Sift4G	Benign	0.28	T
Polyphen		0.17	B
Vest4		0.61
MVP		0.88
MPC		0.26
ClinPred		0.0079	T
GERP RS		6.2
Varity_R		0.16
gMVP		0.93
Mutation Taster		=83/17	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: rs3219155; hg19: chr2-202626242;