rs34946105

Variant names:

• chr2-201715791-C-T
• rs34946105
• NM_020919.4:c.3885G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020919.4(ALS2):​c.3885G>A​(p.Ala1295Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 1,614,196 control chromosomes in the GnomAD database, including 972 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (83 hom., cov: 32)
  • Exomes 𝑓: 0.032 (889 hom.)
• Consequence: ALS2 NM_020919.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.30
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 2-201715791-C-T is Benign according to our data. Variant chr2-201715791-C-T is described in ClinVar as Benign. ClinVar VariationId is 261374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0265 (4039/152322) while in subpopulation SAS AF = 0.0359 (173/4824). AF 95% confidence interval is 0.0325. There are 83 homozygotes in GnomAd4. There are 2001 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 83 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	NM_020919.4	MANE Select	c.3885G>A	p.Ala1295Ala	synonymous	Exon 25 of 34	NP_065970.2
	ALS2	NM_001410975.1		c.3882G>A	p.Ala1294Ala	synonymous	Exon 25 of 34	NP_001397904.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	ENST00000264276.11	TSL:1 MANE Select	c.3885G>A	p.Ala1295Ala	synonymous	Exon 25 of 34	ENSP00000264276.6
	ALS2	ENST00000680497.1		c.3987G>A	p.Ala1329Ala	synonymous	Exon 25 of 34	ENSP00000505954.1
	ALS2	ENST00000679516.1		c.3885G>A	p.Ala1295Ala	synonymous	Exon 24 of 33	ENSP00000505187.1

Frequencies

GnomAD3 genomes AF: 0.0266 AC: 4044 AN: 152204 Hom.: 83 Cov.: 32

Gnomad AFR AF: 0.00555

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.0948

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0362

Gnomad FIN AF: 0.0491

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0344

GnomAD2 exomes AF: 0.0333 AC: 8296 AN: 249356 AF XY: 0.0345

Gnomad AFR exome AF: 0.00484

Gnomad AMR exome AF: 0.0180

Gnomad ASJ exome AF: 0.0944

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0493

Gnomad NFE exome AF: 0.0374

Gnomad OTH exome AF: 0.0367

GnomAD4 exome AF: 0.0321 AC: 46968 AN: 1461874 Hom.: 889 Cov.: 34 AF XY: 0.0327 AC XY: 23771 AN XY: 727240

African (AFR) AF: 0.00463 AC: 155 AN: 33480

American (AMR) AF: 0.0183 AC: 817 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0922 AC: 2409 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.0375 AC: 3238 AN: 86256

European-Finnish (FIN) AF: 0.0477 AC: 2547 AN: 53418

Middle Eastern (MID) AF: 0.0470 AC: 271 AN: 5768

European-Non Finnish (NFE) AF: 0.0319 AC: 35503 AN: 1112002

Other (OTH) AF: 0.0335 AC: 2024 AN: 60394

GnomAD4 genome AF: 0.0265 AC: 4039 AN: 152322 Hom.: 83 Cov.: 32 AF XY: 0.0269 AC XY: 2001 AN XY: 74472

African (AFR) AF: 0.00553 AC: 230 AN: 41572

American (AMR) AF: 0.0229 AC: 351 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0948 AC: 329 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0359 AC: 173 AN: 4824

European-Finnish (FIN) AF: 0.0491 AC: 521 AN: 10608

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0337 AC: 2290 AN: 68032

Other (OTH) AF: 0.0340 AC: 72 AN: 2116

Alfa AF: 0.0298 Hom.: 78

Bravo AF: 0.0244

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.0353

EpiControl AF: 0.0427

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (2)
-	-	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
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.1
DANN	Benign	0.82
PhyloP100		-1.3
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: rs34946105; hg19: chr2-202580514;