rs61745503

Variant names:

• chr2-201761663-C-T
• rs61745503
• NM_020919.4:c.331G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020919.4(ALS2):​c.331G>A​(p.Val111Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,614,166 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V111V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: ALS2 NM_020919.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 1.23
• Publications: 3 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026738793).
• BP6: Variant 2-201761663-C-T is Benign according to our data. Variant chr2-201761663-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 533752.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000178 (260/1461884) while in subpopulation MID AF = 0.00503 (29/5768). AF 95% confidence interval is 0.0036. There are 2 homozygotes in GnomAdExome4. There are 157 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.331G>A	p.Val111Ile	missense	Exon 4 of 34	NP_065970.2
	ALS2	NM_001410975.1		c.331G>A	p.Val111Ile	missense	Exon 4 of 34	NP_001397904.1	A0A7P0T8F3
	ALS2	NM_001135745.2		c.331G>A	p.Val111Ile	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.331G>A	p.Val111Ile	missense	Exon 4 of 34	ENSP00000264276.6	Q96Q42-1
	ALS2	ENST00000467448.5	TSL:1	c.331G>A	p.Val111Ile	missense	Exon 4 of 4	ENSP00000429223.1	Q96Q42-2
	ALS2	ENST00000482789.6	TSL:1	n.673G>A		non_coding_transcript_exon	Exon 4 of 13

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000265 AC: 66 AN: 249374 AF XY: 0.000362

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000178 AC: 260 AN: 1461884 Hom.: 2 Cov.: 38 AF XY: 0.000216 AC XY: 157 AN XY: 727242

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000591 AC: 51 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5768

European-Non Finnish (NFE) AF: 0.0000926 AC: 103 AN: 1112006

Other (OTH) AF: 0.000397 AC: 24 AN: 60396

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74456

African (AFR) AF: 0.0000722 AC: 3 AN: 41550

American (AMR) AF: 0.000131 AC: 2 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000262 Hom.: 0

Bravo AF: 0.000151

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000355 AC: 3

ExAC AF: 0.000273 AC: 33

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	5.6
DANN	Benign	0.75
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.44	N
PhyloP100		1.2
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.090
Sift	Benign	0.40	T
Sift4G	Benign	0.40	T
Polyphen		0.019	B
Vest4		0.047
MVP		0.53
MPC		0.19
ClinPred		0.012	T
GERP RS		0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.43
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61745503; hg19: chr2-202626386;