NM_020919.4:c.2241C>T

Variant names:

• chr2-201741784-G-A
• rs3219160
• NM_020919.4:c.2241C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_020919.4(ALS2):​c.2241C>T​(p.Tyr747Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,614,118 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (14 hom.)
• Consequence: ALS2 NM_020919.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 2.93
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-201741784-G-A is Benign according to our data. Variant chr2-201741784-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241310.
• BP7: Synonymous conserved (PhyloP=2.93 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00202 (308/152280) while in subpopulation AMR AF = 0.00471 (72/15284). AF 95% confidence interval is 0.00384. There are 2 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	NM_020919.4	MANE Select	c.2241C>T	p.Tyr747Tyr	synonymous	Exon 11 of 34	NP_065970.2
	ALS2	NM_001410975.1		c.2241C>T	p.Tyr747Tyr	synonymous	Exon 11 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.2241C>T	p.Tyr747Tyr	synonymous	Exon 11 of 34	ENSP00000264276.6
	ALS2	ENST00000482789.6	TSL:1	n.2583C>T		non_coding_transcript_exon	Exon 11 of 13
	ALS2	ENST00000482891.6	TSL:1	n.2583C>T		non_coding_transcript_exon	Exon 11 of 22

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 308 AN: 152162 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00179 AC: 447 AN: 249086 AF XY: 0.00173

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00271

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00259 AC: 3786 AN: 1461838 Hom.: 14 Cov.: 31 AF XY: 0.00257 AC XY: 1866 AN XY: 727216

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.00286 AC: 128 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000650 AC: 17 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000533 AC: 46 AN: 86250

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53410

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00310 AC: 3446 AN: 1111986

Other (OTH) AF: 0.00197 AC: 119 AN: 60392

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152280 Hom.: 2 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74464

African (AFR) AF: 0.000626 AC: 26 AN: 41556

American (AMR) AF: 0.00471 AC: 72 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00290 AC: 197 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00247 Hom.: 1

Bravo AF: 0.00215

EpiCase AF: 0.00300

EpiControl AF: 0.00397

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	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	-0.45
CADD	Benign	7.6
DANN	Benign	0.54
PhyloP100		2.9
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3219160; hg19: chr2-202606507;