chr2-201718172-A-C

Variant names:

• chr2-201718172-A-C
• rs3219166
• NM_020919.4:c.3741T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_020919.4(ALS2):​c.3741T>G​(p.Gly1247Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,613,580 control chromosomes in the GnomAD database, including 4 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 0.0011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: ALS2 NM_020919.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: -0.0120
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 2-201718172-A-C is Benign according to our data. Variant chr2-201718172-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 417159.
• BP7: Synonymous conserved (PhyloP=-0.012 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0011 (167/152282) while in subpopulation NFE AF = 0.00218 (148/68022). AF 95% confidence interval is 0.00189. There are 0 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.3741T>G	p.Gly1247Gly	synonymous	Exon 24 of 34	NP_065970.2
	ALS2	NM_001410975.1		c.3741T>G	p.Gly1247Gly	synonymous	Exon 24 of 34	NP_001397904.1	A0A7P0T8F3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	ENST00000264276.11	TSL:1 MANE Select	c.3741T>G	p.Gly1247Gly	synonymous	Exon 24 of 34	ENSP00000264276.6	Q96Q42-1
	ALS2	ENST00000680497.1		c.3843T>G	p.Gly1281Gly	synonymous	Exon 24 of 34	ENSP00000505954.1	A0A7P0Z4F3
	ALS2	ENST00000905985.1		c.3834T>G	p.Gly1278Gly	synonymous	Exon 25 of 35	ENSP00000576044.1

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 152164 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00218

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00101 AC: 253 AN: 249488 AF XY: 0.000938

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00197

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.00132 AC: 1926 AN: 1461298 Hom.: 4 Cov.: 31 AF XY: 0.00122 AC XY: 890 AN XY: 727010

African (AFR) AF: 0.000239 AC: 8 AN: 33468

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53402

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

European-Non Finnish (NFE) AF: 0.00164 AC: 1827 AN: 1111532

Other (OTH) AF: 0.000845 AC: 51 AN: 60376

GnomAD4 genome AF: 0.00110 AC: 167 AN: 152282 Hom.: 0 Cov.: 31 AF XY: 0.000980 AC XY: 73 AN XY: 74454

African (AFR) AF: 0.000241 AC: 10 AN: 41554

American (AMR) AF: 0.000392 AC: 6 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00218 AC: 148 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00174 Hom.: 0

Bravo AF: 0.00112

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00249

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	1	ALS2-related disorder (2)
-	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
BayesDel_noAF	Benign	-0.59
CADD	Benign	3.4
DANN	Benign	0.71
PhyloP100		-0.012
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs3219166; hg19: chr2-202582895; COSMIC: COSV108046363;