NM_020919.4:c.2992C>A

Variant names:

• chr2-201726854-G-T
• rs121908137
• NM_020919.4:c.2992C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020919.4(ALS2):​c.2992C>A​(p.Arg998Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000821 in 1,461,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ALS2 NM_020919.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.99
• Publications: 6 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).

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.2992C>A	p.Arg998Arg	synonymous	Exon 18 of 34	NP_065970.2
	ALS2	NM_001410975.1		c.2992C>A	p.Arg998Arg	synonymous	Exon 18 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.2992C>A	p.Arg998Arg	synonymous	Exon 18 of 34	ENSP00000264276.6
	ALS2	ENST00000482891.6	TSL:1	n.3760C>A		non_coding_transcript_exon	Exon 17 of 22
	ALS2	ENST00000680497.1		c.3094C>A	p.Arg1032Arg	synonymous	Exon 18 of 34	ENSP00000505954.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000393 AC: 97 AN: 246852 AF XY: 0.000268

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.000224

Gnomad FIN exome AF: 0.00103

Gnomad NFE exome AF: 0.000304

Gnomad OTH exome AF: 0.000504

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461002 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 726820

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.000170 AC: 9 AN: 52972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111804

Other (OTH) AF: 0.0000166 AC: 1 AN: 60278

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	9.0
DANN	Benign	0.62
PhyloP100		5.0
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs121908137; hg19: chr2-202591577; COSMIC: COSV51887302; COSMIC: COSV51887302;