2-201760892-C-T

Variant names:

• chr2-201760892-C-T
• rs3219156
• NM_020919.4:c.1102G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020919.4(ALS2):​c.1102G>A​(p.Val368Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.902 in 1,612,470 control chromosomes in the GnomAD database, including 657,112 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (58538 hom., cov: 32)
  • Exomes 𝑓: 0.90 (598574 hom.)
• Consequence: ALS2 NM_020919.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -1.95
• Publications: 51 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2400155E-6).
• BP6: Variant 2-201760892-C-T is Benign according to our data. Variant chr2-201760892-C-T is described in ClinVar as Benign. ClinVar VariationId is 261364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

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.1102G>A	p.Val368Met	missense	Exon 4 of 34	NP_065970.2
	ALS2	NM_001410975.1		c.1102G>A	p.Val368Met	missense	Exon 4 of 34	NP_001397904.1	A0A7P0T8F3
	ALS2	NM_001135745.2		c.1102G>A	p.Val368Met	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.1102G>A	p.Val368Met	missense	Exon 4 of 34	ENSP00000264276.6	Q96Q42-1
	ALS2	ENST00000467448.5	TSL:1	c.1102G>A	p.Val368Met	missense	Exon 4 of 4	ENSP00000429223.1	Q96Q42-2
	ALS2	ENST00000482789.6	TSL:1	n.1444G>A		non_coding_transcript_exon	Exon 4 of 13

Frequencies

GnomAD3 genomes AF: 0.875 AC: 133098 AN: 152118 Hom.: 58495 Cov.: 32

Gnomad AFR AF: 0.789

Gnomad AMI AF: 0.941

Gnomad AMR AF: 0.909

Gnomad ASJ AF: 0.902

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.951

Gnomad FIN AF: 0.926

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.895

Gnomad OTH AF: 0.866

GnomAD2 exomes AF: 0.913 AC: 227612 AN: 249212 AF XY: 0.916

Gnomad AFR exome AF: 0.783

Gnomad AMR exome AF: 0.934

Gnomad ASJ exome AF: 0.903

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.921

Gnomad NFE exome AF: 0.901

Gnomad OTH exome AF: 0.909

GnomAD4 exome AF: 0.905 AC: 1321448 AN: 1460234 Hom.: 598574 Cov.: 58 AF XY: 0.906 AC XY: 658222 AN XY: 726114

African (AFR) AF: 0.788 AC: 26340 AN: 33418

American (AMR) AF: 0.931 AC: 41566 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.902 AC: 23564 AN: 26120

East Asian (EAS) AF: 1.00 AC: 39644 AN: 39660

South Asian (SAS) AF: 0.948 AC: 81766 AN: 86234

European-Finnish (FIN) AF: 0.921 AC: 49178 AN: 53406

Middle Eastern (MID) AF: 0.877 AC: 5054 AN: 5764

European-Non Finnish (NFE) AF: 0.900 AC: 999844 AN: 1110634

Other (OTH) AF: 0.903 AC: 54492 AN: 60328

GnomAD4 genome AF: 0.875 AC: 133197 AN: 152236 Hom.: 58538 Cov.: 32 AF XY: 0.879 AC XY: 65395 AN XY: 74434

African (AFR) AF: 0.789 AC: 32744 AN: 41498

American (AMR) AF: 0.909 AC: 13907 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.902 AC: 3131 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5183 AN: 5188

South Asian (SAS) AF: 0.952 AC: 4595 AN: 4828

European-Finnish (FIN) AF: 0.926 AC: 9817 AN: 10606

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.895 AC: 60876 AN: 68022

Other (OTH) AF: 0.868 AC: 1834 AN: 2114

Alfa AF: 0.890 Hom.: 232228

Bravo AF: 0.870

TwinsUK AF: 0.896 AC: 3324

ALSPAC AF: 0.904 AC: 3483

ESP6500AA AF: 0.782 AC: 2997

ESP6500EA AF: 0.898 AC: 7442

ExAC AF: 0.910 AC: 109982

Asia WGS AF: 0.971 AC: 3375 AN: 3478

EpiCase AF: 0.894

EpiControl AF: 0.897

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	2	Amyotrophic lateral sclerosis type 2, juvenile (2)
-	-	2	Infantile-onset ascending hereditary spastic paralysis (2)
-	-	1	ALS2-related disorder (1)
-	-	1	Juvenile primary lateral sclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.0050
DANN	Benign	0.50
DEOGEN2	Benign	0.081	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.076	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-2.0
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.021
Sift	Benign	0.19	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.024
MPC		0.23
ClinPred		0.0022	T
GERP RS		-3.8
Varity_R		0.019
gMVP		0.17
Mutation Taster		=99/1	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: rs3219156; hg19: chr2-202625615; COSMIC: COSV107260573; COSMIC: COSV107260573;